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Bai XF, Ma JC, Zhang C, Chen Z, He J, Cheng SX, Zhang XZ. Click Chemistry-Assisted Rejuvenation of Aging T Cells Sensitizes Aged Mice to Tumor Immunotherapy. J Am Chem Soc 2025; 147:16694-16704. [PMID: 40310278 DOI: 10.1021/jacs.5c05312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2025]
Abstract
Enormous resources have been devoted to address the suboptimal response of tumor patients to immunotherapy. However, a crucial yet often overlooked factor in these effects is the strong correlation between the occurrence and development of tumors and the immune dysfunction associated with aging. Our study aims to rejuvenate aging T cells within tumor-draining lymph nodes (TdLNs) by using targeted delivery of rapamycin, a macrolide capable of mitigating aging-related decline in immune function, thereby enhancing the antitumor efficacy of immunotherapy in aged mice. The targeted delivery system relies on a bioorthogonal reaction that harnesses the click chemistry between the azide (N3) groups artificially introduced onto TdLNs and the dibenzocyclooctyne (DBCO) groups attached to the rapamycin-loaded micelles administered intradermally. Experimental data demonstrate that this approach has effectively restored the functionality of impaired CD8+ T cells in aged mice, thereby enhancing the antitumor response to immune checkpoint blockade (ICB) therapy to levels comparable to those in young mice. This study presents a promising strategy to combat the resistance to immunotherapeutic approaches commonly encountered among elderly tumor patients.
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Affiliation(s)
- Xue-Feng Bai
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Jun-Chi Ma
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Cheng Zhang
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Zhu Chen
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Jinlian He
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Si-Xue Cheng
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China
| | - Xian-Zheng Zhang
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Department of Traditional Chinese Medicine of Zhongnan Hospital, Wuhan University, Wuhan 430072, P. R. China
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2
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Chang J, Campbell-Hanson KR, Vanneste M, Bartschat NI, Nagel R, Arnadottir AK, Vu HN, Montgomery C, Yevdash J, Jiang J, Bhinu A, Helverson A, Henry MD, Steingrímsson E, Weigel RJ, Cornell RA, Kenny C. Antagonistic roles for MITF and TFE3 in melanoma plasticity. Cell Rep 2025; 44:115474. [PMID: 40138313 DOI: 10.1016/j.celrep.2025.115474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 01/06/2025] [Accepted: 03/05/2025] [Indexed: 03/29/2025] Open
Abstract
Melanoma cells can switch from a melanocytic and proliferative state to a mesenchymal and invasive state and back again. This plasticity drives intratumoral heterogeneity, progression, and therapeutic resistance. Microphthalmia-associated transcription factor (MITF) promotes the melanocytic/proliferative phenotype, but factors that drive the mesenchymal/invasive phenotype and the mechanisms that effect the switch between cell states are unclear. Here, we identify the MITF paralog, TFE3, and the non-canonical mTORC1 pathway as regulators of the mesenchymal state. We show that TFE3 expression drives the metastatic phenotype in melanoma cell lines and tumors. Deletion of TFE3 in MITF-low melanoma cell lines suppresses their ability to migrate and metastasize. Further, MITF suppresses the mesenchymal phenotype by directly or indirectly activating expression of FNIP1, FNIP2, and FLCN, which encode components of the non-canonical mTORC1 pathway, thereby promoting cytoplasmic retention and lysosome-mediated degradation of TFE3. These findings highlight a molecular pathway controlling melanoma plasticity and invasiveness.
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Affiliation(s)
- Jeremy Chang
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | | | - Marion Vanneste
- Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Nicholas I Bartschat
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Ryan Nagel
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Asdis K Arnadottir
- Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Hong Nhung Vu
- Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Collin Montgomery
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Julius Yevdash
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Jiarui Jiang
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Ardith Bhinu
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Annika Helverson
- Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA, USA
| | - Michael D Henry
- Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Eiríkur Steingrímsson
- Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Ronald J Weigel
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Robert A Cornell
- Department of Oral Health Sciences, University of Washington, School of Dentistry, Seattle, WA, USA
| | - Colin Kenny
- Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
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Stojchevski R, Sutanto EA, Sutanto R, Hadzi-Petrushev N, Mladenov M, Singh SR, Sinha JK, Ghosh S, Yarlagadda B, Singh KK, Verma P, Sengupta S, Bhaskar R, Avtanski D. Translational Advances in Oncogene and Tumor-Suppressor Gene Research. Cancers (Basel) 2025; 17:1008. [PMID: 40149342 PMCID: PMC11940485 DOI: 10.3390/cancers17061008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/10/2025] [Accepted: 03/15/2025] [Indexed: 03/29/2025] Open
Abstract
Cancer, characterized by the uncontrolled proliferation of cells, is one of the leading causes of death globally, with approximately one in five people developing the disease in their lifetime. While many driver genes were identified decades ago, and most cancers can be classified based on morphology and progression, there is still a significant gap in knowledge about genetic aberrations and nuclear DNA damage. The study of two critical groups of genes-tumor suppressors, which inhibit proliferation and promote apoptosis, and oncogenes, which regulate proliferation and survival-can help to understand the genomic causes behind tumorigenesis, leading to more personalized approaches to diagnosis and treatment. Aberration of tumor suppressors, which undergo two-hit and loss-of-function mutations, and oncogenes, activated forms of proto-oncogenes that experience one-hit and gain-of-function mutations, are responsible for the dysregulation of key signaling pathways that regulate cell division, such as p53, Rb, Ras/Raf/ERK/MAPK, PI3K/AKT, and Wnt/β-catenin. Modern breakthroughs in genomics research, like next-generation sequencing, have provided efficient strategies for mapping unique genomic changes that contribute to tumor heterogeneity. Novel therapeutic approaches have enabled personalized medicine, helping address genetic variability in tumor suppressors and oncogenes. This comprehensive review examines the molecular mechanisms behind tumor-suppressor genes and oncogenes, the key signaling pathways they regulate, epigenetic modifications, tumor heterogeneity, and the drug resistance mechanisms that drive carcinogenesis. Moreover, the review explores the clinical application of sequencing techniques, multiomics, diagnostic procedures, pharmacogenomics, and personalized treatment and prevention options, discussing future directions for emerging technologies.
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Affiliation(s)
- Radoslav Stojchevski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, New York, NY 10022, USA;
- Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | - Edward Agus Sutanto
- CUNY School of Medicine, The City College of New York, 160 Convent Avenue, New York, NY 10031, USA;
| | - Rinni Sutanto
- New York Institute of Technology College of Osteopathic Medicine, Glen Head, NY 11545, USA;
| | - Nikola Hadzi-Petrushev
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia; (N.H.-P.)
| | - Mitko Mladenov
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia; (N.H.-P.)
| | - Sajal Raj Singh
- GloNeuro, Sector 107, Vishwakarma Road, Noida 201301, Uttar Pradesh, India (J.K.S.)
| | - Jitendra Kumar Sinha
- GloNeuro, Sector 107, Vishwakarma Road, Noida 201301, Uttar Pradesh, India (J.K.S.)
| | - Shampa Ghosh
- GloNeuro, Sector 107, Vishwakarma Road, Noida 201301, Uttar Pradesh, India (J.K.S.)
| | | | - Krishna Kumar Singh
- Symbiosis Centre for Information Technology (SCIT), Rajiv Gandhi InfoTech Park, Hinjawadi, Pune 411057, Maharashtra, India;
| | - Prashant Verma
- School of Management, BML Munjal University, NH8, Sidhrawali, Gurugram 122413, Haryana, India
| | - Sonali Sengupta
- Department of Gastroenterology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India
| | - Rakesh Bhaskar
- School of Chemical Engineering, Yeungnam University, Gyeongsan 38541, Republic of Korea
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Dimiter Avtanski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, New York, NY 10022, USA;
- Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
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Hashemi M, Mohandesi Khosroshahi E, Asadi S, Tanha M, Ghatei Mohseni F, Abdolmohammad Sagha R, Taheri E, Vazayefi P, Shekarriz H, Habibi F, Mortazi S, Khorrami R, Nabavi N, Rashidi M, Taheriazam A, Rahimzadeh P, Entezari M. Emerging roles of non-coding RNAs in modulating the PI3K/Akt pathway in cancer. Noncoding RNA Res 2025; 10:1-15. [PMID: 39296640 PMCID: PMC11406677 DOI: 10.1016/j.ncrna.2024.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 07/25/2024] [Accepted: 08/08/2024] [Indexed: 09/21/2024] Open
Abstract
Cancer progression results from the dysregulation of molecular pathways, each with unique features that can either promote or inhibit tumor growth. The complexity of carcinogenesis makes it challenging for researchers to target all pathways in cancer therapy, emphasizing the importance of focusing on specific pathways for targeted treatment. One such pathway is the PI3K/Akt pathway, which is often overexpressed in cancer. As tumor cells progress, the expression of PI3K/Akt increases, further driving cancer advancement. This study aims to explore how ncRNAs regulate the expression of PI3K/Akt. NcRNAs are found in both the cytoplasm and nucleus, and their functions vary depending on their location. They can bind to the promoters of PI3K or Akt, either reducing or increasing their expression, thus influencing tumorigenesis. The ncRNA/PI3K/Akt axis plays a crucial role in determining cell proliferation, metastasis, epithelial-mesenchymal transition (EMT), and even chemoresistance and radioresistance in human cancers. Anti-tumor compounds can target ncRNAs to modulate the PI3K/Akt axis. Moreover, ncRNAs can regulate the PI3K/Akt pathway both directly and indirectly.
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Affiliation(s)
- Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elaheh Mohandesi Khosroshahi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Saba Asadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mahsa Tanha
- Department of Biological Sciences, University of Alabama, Tuscaloosa, AL, United States
| | - Forough Ghatei Mohseni
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ramina Abdolmohammad Sagha
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elham Taheri
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Paria Vazayefi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Helya Shekarriz
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fatemeh Habibi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Shaghayegh Mortazi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ramin Khorrami
- Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Noushin Nabavi
- Independent Researchers, Victoria, British Columbia, V8V 1P7, Canada
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
- The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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Mallah H, Diabasana Z, Soultani S, Idoux-Gillet Y, Massfelder T. Prostate Cancer: A Journey Through Its History and Recent Developments. Cancers (Basel) 2025; 17:194. [PMID: 39857976 PMCID: PMC11763992 DOI: 10.3390/cancers17020194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 01/01/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
Prostate cancer is one of the most common diseases among men worldwide and continues to pose a serious threat to health. This review shows the history and the new developments in the management of prostate cancer, with an emphasis on a range of therapeutic approaches, such as hormone therapy, radiation therapy, surgery, and innovative targeted therapeutics. The evolution of these treatments is examined in light of clinical outcomes, patient quality of life, and emerging resistance mechanisms, such as the recently shown vitamin D-based strategies. New developments that have the potential to increase survival rates and reduce side effects are also discussed, including PARP inhibitors (PARPis), immunotherapy, and tailored medication. Additionally, the use of biomarkers and sophisticated imaging methods in therapeutic decision-making is explored, with a focus on how these tools might improve patient care. The absolute necessity for a multidisciplinary approach for improving treatment strategies is becoming more and more apparent as our understanding of the biology of prostate cancer deepens. This approach ensures that patients receive customized medicines that fit their unique profiles. Future avenues of investigation will focus on resolving issues dealing with treatment efficacy and resistance to improve treatment results, ultimately leading to disease cure for prostate cancer patients.
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Affiliation(s)
| | | | | | | | - Thierry Massfelder
- Regenerative NanoMedicine, Centre de Recherche en Biomédecine de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), UMR_S U1260 INSERM and University of Strasbourg, 67085 Strasbourg, France; (H.M.); (Z.D.); (Y.I.-G.)
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6
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Yao Z, Chen H. Everolimus in pituitary tumor: a review of preclinical and clinical evidence. Front Endocrinol (Lausanne) 2024; 15:1456922. [PMID: 39736867 PMCID: PMC11682973 DOI: 10.3389/fendo.2024.1456922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Accepted: 11/27/2024] [Indexed: 01/01/2025] Open
Abstract
Although pituitary tumors (PTs) are mostly benign, some PTs are characterized by low surgical resection rates, high recurrence rates, and poor response to conventional treatments and profoundly affect patients' quality of life. Everolimus (EVE) is the only FDA-approved mTOR inhibitor, which can be used for oral treatment. It effectively inhibits tumor cell proliferation and angiogenesis. It has been administered for various neuroendocrine tumors of the digestive tract, lungs, and pancreas. EVE not only suppresses the growth and proliferation of APT cells but also enhances their sensitivity to radiotherapy and chemotherapy. This review introduces the role of the PI3K/AKT/mTOR pathway in the development of APTs, comprehensively explores the current status of preclinical and clinical research of EVE in APTs, and discusses the blood-brain barrier permeability and safety of EVE.
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Affiliation(s)
- Zihong Yao
- The Second Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China
- Department of Endocrinology and Metabolism, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Hui Chen
- Department of Endocrinology and Metabolism, Lanzhou University Second Hospital, Lanzhou, Gansu, China
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Gupta KB, Gao J, Li X, Thangaraju M, Panda SS, Lokeshwar BL. Cytotoxic Autophagy: A Novel Treatment Paradigm against Breast Cancer Using Oleanolic Acid and Ursolic Acid. Cancers (Basel) 2024; 16:3367. [PMID: 39409987 PMCID: PMC11476055 DOI: 10.3390/cancers16193367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 09/26/2024] [Accepted: 09/29/2024] [Indexed: 10/20/2024] Open
Abstract
BACKGROUND Oleanolic acid (OA) and Ursolic acid (UA) are bioactive triterpenoids. Reported activities vary with the dose used for testing their activities in vitro. Studies using doses of ≥20 µM showed apoptosis activities in cancer cells. However, reported drug levels in circulation achieved by oral administration of UA and OA are ≤2 µM, thus limiting their use for treatment or delivering a combination treatment. MATERIALS AND METHODS The present report demonstrates the efficacy of OA, UA, and OA + UA on tumor cell-specific cytotoxicity at low doses (5 µM to 10 µM) in breast cancer (BrCa) cell lines MCF7 and MDA-MB231. RESULTS The data show that both OA and UA killed BrCa cells at low doses, but were significantly less toxic to MCF-12A, a non-tumorigenic cell line. Moreover, OA + UA at ≤10 µM was lethal to BrCa cells. Mechanistic studies unraveled the significant absence of apoptosis, but their cytotoxicity was due to the induction of excessive autophagy at a OA + UA dose of 5 µM each. A link to drug-induced cytotoxic autophagy was established by demonstrating a lack of their cytotoxicity by silencing the autophagy-targeting genes (ATGs), which prevented OA-, UA-, or OA + UA-induced cell death. Further, UA or OA + UA treatment of BrCa cells caused an inhibition of PI3 kinase-mediated phosphorylation of Akt/mTOR, the key pathways that regulate cancer cell survival, metabolism, and proliferation. DISCUSSION Combinations of a PI3K inhibitor (LY294002) with OA, UA, or OA + UA synergistically inhibited BrCa cell survival. Therefore, the dominance of cytotoxic autophagy by inhibiting PI3K-mediated autophagy may be the primary mechanism of PTT-induced anticancer activity in BrCa cells. CONCLUSION These results suggest it would be worthwhile testing combined OA and UA in clinical settings.
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Affiliation(s)
- Kunj Bihari Gupta
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; (K.B.G.); (J.G.); (X.L.)
| | - Jie Gao
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; (K.B.G.); (J.G.); (X.L.)
- Department of Clinical and Diagnostic Science, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Xin Li
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; (K.B.G.); (J.G.); (X.L.)
- The Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA
| | - Muthusamy Thangaraju
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (M.T.); (S.S.P.)
| | - Siva S. Panda
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; (M.T.); (S.S.P.)
- Department of Chemistry and Biochemistry, College of Science and Mathematics, Augusta University, Augusta, GA 30912, USA
| | - Bal L. Lokeshwar
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA; (K.B.G.); (J.G.); (X.L.)
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Gu F, Shen X, Wang Z, Xie Z, Ke N. Preoperative metabolic syndrome and prognosis after pancreatectomy for pancreatic cancer: A retrospective study. World J Surg 2024; 48:2224-2234. [PMID: 38973012 DOI: 10.1002/wjs.12263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 04/24/2024] [Indexed: 07/09/2024]
Abstract
BACKGROUND We conducted a retrospective study to investigate the impact of metabolic syndrome (MetS), its individual components, and the number of metabolic risk factors on the prognosis of pancreatic cancer (PC) following pancreatectomy. METHODS MetS was defined as meeting any three of the following criteria: (1) waist circumference ≥85 cm in men or ≥80 cm in women; (2) triglycerides ≥150 mg/dL or receiving drug treatment for elevated triglycerides; (3) high-density lipoprotein cholesterol <40 mg/dL in men or <50 mg/dL in women or receiving drug treatment for reduced HDL-C; (4) systolic blood pressure ≥130 mmHg and/or diastolic blood pressure ≥85 mmHg or receiving drug treatment for hypertension; and (5) fasting glucose, (FG) ≥100 mg/dL or receiving drug treatment for elevated glucose. The hazard ratio (HR) and 95% confidence interval (CI) were calculated by the Cox regression model. RESULTS Six hundred and seven patients who underwent radical resection for PC were enrolled in this study. Among them, 352 patients presented with preoperative MetS. MetS was associated with shorter overall survival (OS) but not with shorter disease-free survival (DFS). The adjusted HR (95% CI) for the poor OS in patients with 3, 4, and 5 metabolic risk components (vs. ≤ 2) were 1.32 (1.03-1.84), 1.64 (1.18-2.29), and 1.96 (1.27-3.04), respectively (p < 0.05). Elevated FG emerged as a significant predictor for poor OS and DFS. CONCLUSIONS This study highlights that preoperative MetS serves as a significant predictor for OS in patients with PC, with its predictive value escalating as the number of metabolic risk components increases.
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Affiliation(s)
- Fenglin Gu
- Department of General Surgery, Division of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaoding Shen
- Department of General Surgery, Division of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ziyao Wang
- Department of General Surgery, Division of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zerong Xie
- Department of General Surgery, Division of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of General Surgery, West China Tianfu Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Nengwen Ke
- Department of General Surgery, Division of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Yuan R, Adlimoghaddam A, Zhu Y, Han X, Bartke A. Early Life Interventions: Impact on Aging and Longevity. Aging Dis 2024:AD.202.0516. [PMID: 39325935 DOI: 10.14336/ad.202.0516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 07/05/2024] [Indexed: 09/28/2024] Open
Abstract
Across mammals, lifespans vary remarkably, spanning over a hundredfold difference. Comparative studies consistently reveal a strong inverse relationship between developmental pace and lifespan, hinting at the potential for early-life interventions (ELIs) to influence aging and lifespan trajectories. Focusing on postnatal interventions in mice, this review explores how ELIs influence development, lifespan, and the underlying mechanisms. Previous ELI studies have employed a diverse array of approaches, including dietary modifications, manipulations of the somatotropic axis, and various chemical treatments. Notably, these interventions have demonstrated significant impacts on aging and lifespan in mice. The underlying mechanisms likely involve pathways related to mitochondrial function, mTOR and AMPK signaling, cellular senescence, and epigenetic alterations. Interestingly, ELI studies may serve as valuable models for investigating the complex regulatory mechanisms of development and aging, particularly regarding the interplay among somatic growth, sexual maturation, and lifespan. In addition, prior research has highlighted the intricacies of experimental design and data interpretation. Factors such as timing, sex-specific effects, administration methods, and animal husbandry practices must be carefully considered to ensure the reliability and reproducibility of results, as well as rigorous interpretation. Addressing these factors is essential for advancing our understanding of how development, aging, and lifespan are regulated, potentially opening avenues for interventions that promote healthy aging.
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Affiliation(s)
- Rong Yuan
- Division of Geriatrics Research, Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
- Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
| | - Aida Adlimoghaddam
- Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
- Department of Neurology, Center for Alzheimer's Research and Treatment, Neuroscience Institute, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
- Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
| | - Yun Zhu
- Division of Geriatrics Research, Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
| | - Xiuqi Han
- Division of Geriatrics Research, Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
- Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
| | - Andrzej Bartke
- Division of Geriatrics Research, Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
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Singh A, Ravendranathan N, Frisbee JC, Singh KK. Complex Interplay between DNA Damage and Autophagy in Disease and Therapy. Biomolecules 2024; 14:922. [PMID: 39199310 PMCID: PMC11352539 DOI: 10.3390/biom14080922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/19/2024] [Accepted: 07/26/2024] [Indexed: 09/01/2024] Open
Abstract
Cancer, a multifactorial disease characterized by uncontrolled cellular proliferation, remains a global health challenge with significant morbidity and mortality. Genomic and molecular aberrations, coupled with environmental factors, contribute to its heterogeneity and complexity. Chemotherapeutic agents like doxorubicin (Dox) have shown efficacy against various cancers but are hindered by dose-dependent cytotoxicity, particularly on vital organs like the heart and brain. Autophagy, a cellular process involved in self-degradation and recycling, emerges as a promising therapeutic target in cancer therapy and neurodegenerative diseases. Dysregulation of autophagy contributes to cancer progression and drug resistance, while its modulation holds the potential to enhance treatment outcomes and mitigate adverse effects. Additionally, emerging evidence suggests a potential link between autophagy, DNA damage, and caretaker breast cancer genes BRCA1/2, highlighting the interplay between DNA repair mechanisms and cellular homeostasis. This review explores the intricate relationship between cancer, Dox-induced cytotoxicity, autophagy modulation, and the potential implications of autophagy in DNA damage repair pathways, particularly in the context of BRCA1/2 mutations.
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Affiliation(s)
- Aman Singh
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond Street North, London, ON N6A 5C1, Canada; (A.S.); (N.R.); (J.C.F.)
| | - Naresh Ravendranathan
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond Street North, London, ON N6A 5C1, Canada; (A.S.); (N.R.); (J.C.F.)
| | - Jefferson C. Frisbee
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond Street North, London, ON N6A 5C1, Canada; (A.S.); (N.R.); (J.C.F.)
| | - Krishna K. Singh
- Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond Street North, London, ON N6A 5C1, Canada; (A.S.); (N.R.); (J.C.F.)
- Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada
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Verner JM, Arbuthnott HF, Ramachandran R, Bharadwaj M, Chaudhury N, Jou E. Emerging roles of type 1 innate lymphoid cells in tumour pathogenesis and cancer immunotherapy. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:296-315. [PMID: 38745765 PMCID: PMC11090689 DOI: 10.37349/etat.2024.00219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 12/14/2023] [Indexed: 05/16/2024] Open
Abstract
Innate lymphoid cells (ILCs) are the most recently discovered class of innate immune cells found to have prominent roles in various human immune-related pathologies such as infection and autoimmune diseases. However, their role in cancer was largely unclear until recently, where several emerging studies over the past few years unanimously demonstrate ILCs to be critical players in tumour immunity. Being the innate counterpart of T cells, ILCs are potent cytokine producers through which they orchestrate the overall immune response upstream of adaptive immunity thereby modulating T cell function. Out of the major ILC subsets, ILC1s have gained significant traction as potential immunotherapeutic candidates due to their central involvement with the anti-tumour type 1 immune response. ILC1s are potent producers of the well-established anti-tumour cytokine interferon γ (IFNγ), and exert direct cytotoxicity against cancer cells in response to the cytokine interleukin-15 (IL-15). However, in advanced diseases, ILC1s are found to demonstrate an exhausted phenotype in the tumour microenvironment (TME) with impaired effector functions, characterised by decreased responsiveness to cytokines and reduced IFNγ production. Tumour cells produce immunomodulatory cytokines such as transforming growth factor β (TGFβ) and IL-23, and through these suppress ILC1 anti-tumour actfivities and converts ILC1s to pro-tumoural ILC3s respectively, resulting in disease progression. This review provides a comprehensive overview of ILC1s in tumour immunity, and discusses the exciting prospects of harnessing ILC1s for cancer immunotherapy, either alone or in combination with cytokine-based treatment. The exciting prospects of targeting the upstream innate immune system through ILC1s may surmount the limitations associated with adaptive immune T cell-based strategies used in the clinic currently, and overcome cancer immunotherapeutic resistance.
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Affiliation(s)
| | | | - Raghavskandhan Ramachandran
- Medical Sciences Division, Oxford University Hospitals, OX3 9DU Oxford, United Kingdom
- Balliol College, University of Oxford, OX1 3BJ Oxford, United Kingdom
| | - Manini Bharadwaj
- Wexham Park Hospital, Frimley Health NHS Foundation Trust, SL2 4HL Slough, United Kingdom
| | - Natasha Chaudhury
- Wexham Park Hospital, Frimley Health NHS Foundation Trust, SL2 4HL Slough, United Kingdom
| | - Eric Jou
- Medical Sciences Division, Oxford University Hospitals, OX3 9DU Oxford, United Kingdom
- Wexham Park Hospital, Frimley Health NHS Foundation Trust, SL2 4HL Slough, United Kingdom
- Kellogg College, University of Oxford, OX2 6PN Oxford, United Kingdom
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12
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Verner JM, Arbuthnott HF, Ramachandran R, Bharadwaj M, Chaudhury N, Jou E. Emerging roles of type 1 innate lymphoid cells in tumour pathogenesis and cancer immunotherapy. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:296-315. [DOI: 10.37349/etat.2023.00219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 12/14/2023] [Indexed: 01/04/2025] Open
Abstract
Innate lymphoid cells (ILCs) are the most recently discovered class of innate immune cells found to have prominent roles in various human immune-related pathologies such as infection and autoimmune diseases. However, their role in cancer was largely unclear until recently, where several emerging studies over the past few years unanimously demonstrate ILCs to be critical players in tumour immunity. Being the innate counterpart of T cells, ILCs are potent cytokine producers through which they orchestrate the overall immune response upstream of adaptive immunity thereby modulating T cell function. Out of the major ILC subsets, ILC1s have gained significant traction as potential immunotherapeutic candidates due to their central involvement with the anti-tumour type 1 immune response. ILC1s are potent producers of the well-established anti-tumour cytokine interferon γ (IFNγ), and exert direct cytotoxicity against cancer cells in response to the cytokine interleukin-15 (IL-15). However, in advanced diseases, ILC1s are found to demonstrate an exhausted phenotype in the tumour microenvironment (TME) with impaired effector functions, characterised by decreased responsiveness to cytokines and reduced IFNγ production. Tumour cells produce immunomodulatory cytokines such as transforming growth factor β (TGFβ) and IL-23, and through these suppress ILC1 anti-tumour actfivities and converts ILC1s to pro-tumoural ILC3s respectively, resulting in disease progression. This review provides a comprehensive overview of ILC1s in tumour immunity, and discusses the exciting prospects of harnessing ILC1s for cancer immunotherapy, either alone or in combination with cytokine-based treatment. The exciting prospects of targeting the upstream innate immune system through ILC1s may surmount the limitations associated with adaptive immune T cell-based strategies used in the clinic currently, and overcome cancer immunotherapeutic resistance.
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Affiliation(s)
| | | | - Raghavskandhan Ramachandran
- Medical Sciences Division, Oxford University Hospitals, OX3 9DU Oxford, United Kingdom; Balliol College, University of Oxford, OX1 3BJ Oxford, United Kingdom
| | - Manini Bharadwaj
- exham Park Hospital, Frimley Health NHS Foundation Trust, SL2 4HL Slough, United Kingdom
| | - Natasha Chaudhury
- exham Park Hospital, Frimley Health NHS Foundation Trust, SL2 4HL Slough, United Kingdom
| | - Eric Jou
- Medical Sciences Division, Oxford University Hospitals, OX3 9DU Oxford, United Kingdom; Wexham Park Hospital, Frimley Health NHS Foundation Trust, SL2 4HL Slough, United Kingdom; Kellogg College, University of Oxford, OX2 6PN Oxford, United Kingdom
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13
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Thakur A, Rana N, Kumar R. Altered hormone expression induced genetic changes leads to breast cancer. Curr Opin Oncol 2024; 36:115-122. [PMID: 38441060 DOI: 10.1097/cco.0000000000001019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2024]
Abstract
PURPOSE OF REVIEW Breast cancer ranks first among gynecological cancer in India. It is associated with urbanization, changes in lifestyle and obesity. Hormones also play a crucial role in the development of breast cancer. Steroid hormones play critical role in development of breast cancer. RECENT FINDING Breast cancer is caused due to alteration in different hormone expressions leading to genetic instability. Loss or gains of functions due to genetic instability were associated with the alterations in housekeeping genes. Up-regulation in c-myc, signal transducer and activator of transcription (STAT), CREB-regulated transcription coactivator (CRTC), and eukaryotic translation initiation factor 4E (eIF4E) may cause the development of breast cancer. Peptide hormones are commonly following the phosphoinositide 3-kinases (PI3K) pathway for activation of cell cycle causing uncontrolled proliferation. Although steroid hormones are following the Ras/Raf/mitogen-activated protein kinase (MEK) pathway, their hyper-activation of these pathways causes extracellular-signal-regulated kinase (ERK) and MAPK activation, leading to carcinogenesis. SUMMARY Alteration in cell cycle proteins, oncogenes, tumor suppressor genes, transcription and translation factors lead to breast cancer. Apoptosis plays a vital role in the elimination of abnormal cells but failure in any of these apoptotic pathways may cause tumorigenesis. Hence, a complex interplay of hormonal and genetic factors is required to maintain homeostasis in breast cells. Imbalance in homeostasis of these hormone and genes may lead to breast cancer.
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Affiliation(s)
- Anchal Thakur
- Department of Animal sciences, Central University of Himachal Pradesh, Dharamshala, H.P
| | - Navya Rana
- Department of Animal sciences, Central University of Himachal Pradesh, Dharamshala, H.P
| | - Ranjit Kumar
- Department of Zoology, Nagaland University, Lumami, Nagaland
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Jacobs RQ, Schneider DA. Transcription elongation mechanisms of RNA polymerases I, II, and III and their therapeutic implications. J Biol Chem 2024; 300:105737. [PMID: 38336292 PMCID: PMC10907179 DOI: 10.1016/j.jbc.2024.105737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 01/30/2024] [Accepted: 02/01/2024] [Indexed: 02/12/2024] Open
Abstract
Transcription is a tightly regulated, complex, and essential cellular process in all living organisms. Transcription is comprised of three steps, transcription initiation, elongation, and termination. The distinct transcription initiation and termination mechanisms of eukaryotic RNA polymerases I, II, and III (Pols I, II, and III) have long been appreciated. Recent methodological advances have empowered high-resolution investigations of the Pols' transcription elongation mechanisms. Here, we review the kinetic similarities and differences in the individual steps of Pol I-, II-, and III-catalyzed transcription elongation, including NTP binding, bond formation, pyrophosphate release, and translocation. This review serves as an important summation of Saccharomyces cerevisiae (yeast) Pol I, II, and III kinetic investigations which reveal that transcription elongation by the Pols is governed by distinct mechanisms. Further, these studies illustrate how basic, biochemical investigations of the Pols can empower the development of chemotherapeutic compounds.
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Affiliation(s)
- Ruth Q Jacobs
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - David A Schneider
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
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15
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Coleman N, Stephen B, Fu S, Karp D, Subbiah V, Ahnert JR, Piha‐Paul SA, Wright J, Fessahaye SN, Ouyang F, Yilmaz B, Meric‐Bernstam F, Naing A. Phase I study of sapanisertib (CB-228/TAK-228/MLN0128) in combination with ziv-aflibercept in patients with advanced solid tumors. Cancer Med 2024; 13:e6877. [PMID: 38400671 PMCID: PMC10891443 DOI: 10.1002/cam4.6877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 11/01/2023] [Accepted: 11/27/2023] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND Sapanisertib is a potent ATP-competitive, dual inhibitor of mTORC1/2. Ziv-aflibercept is a recombinant fusion protein comprising human VEGF receptor extracellular domains fused to human immunoglobulin G1. HIF-1α inhibition in combination with anti-angiogenic therapy is a promising anti-tumor strategy. This Phase 1 dose-escalation/expansion study assessed safety/ tolerability of sapanisertib in combination with ziv-aflibercept in advanced solid tumors. METHODS Fifty-five patients with heavily pre-treated advanced metastatic solid tumors resistant or refractory to standard treatment received treatment on a range of dose levels. RESULTS Fifty-five patients were enrolled and treated across a range of dose levels. Forty were female (73%), median age was 62 (range: 21-79), and ECOG PS was 0 (9, 16%) or 1 (46, 84%). Most common tumor types included ovarian (8), colorectal (8), sarcoma (8), breast (3), cervical (4), and endometrial (4). Median number of prior lines of therapy was 4 (range 2-11). Sapanisertib 4 mg orally 3 days on and 4 days off plus 3 mg/kg ziv-aflibercept IV every 2 weeks on a 28-day cycle was defined as the maximum tolerated dose. Most frequent treatment-related grade ≥2 adverse events included hypertension, fatigue, anorexia, hypertriglyceridemia, diarrhea, nausea, mucositis, and serum lipase increase. There were no grade 5 events. In patients with evaluable disease (n = 50), 37 patients (74%) achieved stable disease (SD) as best response, two patients (4%) achieved a confirmed partial response (PR); disease control rate (DCR) (CR + SD + PR) was 78%. CONCLUSION The combination of sapanisertib and ziv-aflibercept was generally tolerable and demonstrated anti-tumor activity in heavily pre-treated patients with advanced malignancies.
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Affiliation(s)
- Niamh Coleman
- Department of Investigational Cancer TherapeuticsThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
- Present address:
Department of Medical OncologyTrinity St. James' Cancer Institute, St. James's Hospital Trinity College MedicineDublinIreland
| | - Bettzy Stephen
- Department of Investigational Cancer TherapeuticsThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Siqing Fu
- Department of Investigational Cancer TherapeuticsThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Daniel Karp
- Department of Investigational Cancer TherapeuticsThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Vivek Subbiah
- Early Phase Drug DevelopmentSarah Cannon Research InstituteNashvilleTennesseeUSA
| | - Jordi Rodon Ahnert
- Department of Investigational Cancer TherapeuticsThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Sarina A. Piha‐Paul
- Department of Investigational Cancer TherapeuticsThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - John Wright
- National Cancer Institute (NCI), Cancer Therapy Evaluation Program (CTEP)BethesdaMarylandUSA
| | - Senait N. Fessahaye
- Department of Investigational Cancer TherapeuticsThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Fengying Ouyang
- Department of Investigational Cancer TherapeuticsThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Bulent Yilmaz
- Department of Investigational Cancer TherapeuticsThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
| | - Funda Meric‐Bernstam
- Department of Investigational Cancer TherapeuticsThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
- Khalifa Institute for Personalized Cancer TherapyMD Anderson Cancer CenterHoustonTexasUSA
- Department of Surgical OncologyMD Anderson Cancer CenterHoustonTexasUSA
| | - Aung Naing
- Department of Investigational Cancer TherapeuticsThe University of Texas MD Anderson Cancer CenterHoustonTexasUSA
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16
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Zhang L, Zhai BZ, Wu YJ, Wang Y. Recent progress in the development of nanomaterials targeting multiple cancer metabolic pathways: a review of mechanistic approaches for cancer treatment. Drug Deliv 2023; 30:1-18. [PMID: 36597205 PMCID: PMC9943254 DOI: 10.1080/10717544.2022.2144541] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Cancer is a very heterogeneous disease, and uncontrolled cell division is the main characteristic of cancer. Cancerous cells need a high nutrition intake to enable aberrant growth and survival. To do so, cancer cells modify metabolic pathways to produce energy and anabolic precursors and preserve redox balance. Due to the importance of metabolic pathways in tumor growth and malignant transformation, metabolic pathways have also been given promising perspectives for cancer treatment, providing more effective treatment strategies, and target-specific with minimum side effects. Metabolism-based therapeutic nanomaterials for targeted cancer treatment are a promising option. Numerous types of nanoparticles (NPs) are employed in the research and analysis of various cancer therapies. The current review focuses on cutting-edge strategies and current cancer therapy methods based on nanomaterials that target various cancer metabolisms. Additionally, it highlighted the primacy of NPs-based cancer therapies over traditional ones, the challenges, and the future potential.
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Affiliation(s)
- Ling Zhang
- Reproductive Medicine Center, Department of Reproductive Endocrinology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China,CONTACT Ling Zhang Reproductive Medicine Center, Department of Reproductive Endocrinology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, No. 158 Shangtang Road, Hangzhou310014, Zhejiang, China
| | - Bing-Zhong Zhai
- Hangzhou Municipal Center for Disease Control and Prevention, Hangzhou, Zhejiang, 310021, China
| | - Yue-Jin Wu
- Institute of Food Science and Engineering, Hangzhou Medical College, Hangzhou, Zhejiang, 310013, China
| | - Yin Wang
- Institute of Food Science and Engineering, Hangzhou Medical College, Hangzhou, Zhejiang, 310013, China,; Yin Wang Institute of Food Science and Engineering, Hangzhou Medical College, 182 Tianmushan Road, Hangzhou310013, Zhejiang, China
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Murali R, Gopalakrishnan AV. Molecular insight into renal cancer and latest therapeutic approaches to tackle it: an updated review. Med Oncol 2023; 40:355. [PMID: 37955787 DOI: 10.1007/s12032-023-02225-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 10/16/2023] [Indexed: 11/14/2023]
Abstract
Renal cell carcinoma (RCC) is one of the most lethal genitourinary cancers, with the highest mortality rate, and may remain undetected throughout its development. RCC can be sporadic or hereditary. Exploring the underlying genetic abnormalities in RCC will have important implications for understanding the origins of nonhereditary renal cancers. The treatment of RCC has evolved over centuries from the era of cytokines to targeted therapy to immunotherapy. A surgical cure is the primary treatment modality, especially for organ-confined diseases. Furthermore, the urologic oncology community focuses on nephron-sparing surgical approaches and ablative procedures when small renal masses are detected incidentally in conjunction with interventional radiologists. In addition to new combination therapies approved for RCC treatment, several trials have been conducted to investigate the potential benefits of certain drugs. This may lead to durable responses and more extended survival benefits for patients with metastatic RCC (mRCC). Several approved drugs have reduced the mortality rate of patients with RCC by targeting VEGF signaling and mTOR. This review better explains the signaling pathways involved in the RCC progression, oncometabolites, and essential biomarkers in RCC that can be used for its diagnosis. Further, it provides an overview of the characteristics of RCC carcinogenesis to assist in combating treatment resistance, as well as details about the current management and future therapeutic options. In the future, multimodal and integrated care will be available, with new treatment options emerging as we learn more about the disease.
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Affiliation(s)
- Reshma Murali
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology VIT, Vellore, Tamil Nadu, 632014, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology VIT, Vellore, Tamil Nadu, 632014, India.
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18
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Liu D, Wang Y, Li X, Wang Y, Zhang Z, Wang Z, Zhang X. Participation of protein metabolism in cancer progression and its potential targeting for the management of cancer. Amino Acids 2023; 55:1223-1246. [PMID: 37646877 DOI: 10.1007/s00726-023-03316-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 08/11/2023] [Indexed: 09/01/2023]
Abstract
Cancer malignancies may broadly be described as heterogeneous disorders manifested by uncontrolled cellular growth/division and proliferation. Tumor cells utilize metabolic reprogramming to accomplish the upregulated nutritional requirements for sustaining their uncontrolled growth, proliferation, and survival. Metabolic reprogramming also called altered or dysregulated metabolism undergoes modification in normal metabolic pathways for anabolic precursor's generation that serves to continue biomass formation that sustains the growth, proliferation, and survival of carcinogenic cells under a nutrition-deprived microenvironment. A wide range of dysregulated/altered metabolic pathways encompassing different metabolic regulators have been described; however, the current review is focused to explain deeply the metabolic pathways modifications inducing upregulation of proteins/amino acids metabolism. The essential modification of various metabolic cycles with their consequent outcomes meanwhile explored promising therapeutic targets playing a pivotal role in metabolic regulation and is successfully employed for effective target-specific cancer treatment. The current review is aimed to understand the metabolic reprogramming of different proteins/amino acids involved in tumor progression along with potential therapeutic perspective elucidating targeted cancer therapy via these targets.
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Affiliation(s)
- Dalong Liu
- Department of Orthopedics, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, 130000, China
| | - Yun Wang
- Department of Thoracic Surgery, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, 130000, China
| | - Xiaojiang Li
- Department of Orthopedics, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, 130000, China
| | - Yan Wang
- Department of Neurosurgery, People's Hospital of Jilin City, Jilin, 136200, China
| | - Zhiqiang Zhang
- Department of Orthopedics, Baishan Hospital of Traditional Chinese Medicine, Baishan, 134300, China
| | - Zhifeng Wang
- Department of Traditional Chinese Medicine, Changchun Chaoyang District Hospital of Traditional Chinese Medicine, Changchun, 130000, China
| | - Xudong Zhang
- Department of Brain Surgery, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, 130000, China.
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Su WY, Tian LY, Guo LP, Huang LQ, Gao WY. PI3K signaling-regulated metabolic reprogramming: From mechanism to application. Biochim Biophys Acta Rev Cancer 2023; 1878:188952. [PMID: 37499988 DOI: 10.1016/j.bbcan.2023.188952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 07/04/2023] [Accepted: 07/05/2023] [Indexed: 07/29/2023]
Abstract
Oncogenic signaling involved in tumor metabolic reprogramming. Tumorigenesis was not only determined by the mutations or deletion of oncogenes but also accompanied by the reprogramming of cellular metabolism. Metabolic alterations play a crucial regulatory role in the development and progression of tumors. Oncogenic PI3K/AKT signaling mediates the metabolic switch in cancer cells and immune cells in the tumor microenvironment. PI3K/AKT and its downstream effector branch off and connect to multiple steps of metabolism, such as glucose, lipids, and amino acids. Thus, PI3K inhibitor could effectively regulate metabolic pathway and impede the oncogenic process and some key metabolic proteins or critical enzymes also constitute biomarkers for tumor diagnosis and treatment. In the current review, we summarize the significant effect of PI3K/AKT signaling toward tumor metabolism, it enables us to obtain the better understanding for this interaction and develop more effective therapeutic strategies targeting cancer cell metabolism.
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Affiliation(s)
- Wen Ya Su
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Lu Yao Tian
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Lan Pin Guo
- National Resource Center for Chinese Materia Medica, Chinese Academy of Chinese Medical Sciences, Beijing, China
| | - Lu Qi Huang
- National Resource Center for Chinese Materia Medica, Chinese Academy of Chinese Medical Sciences, Beijing, China
| | - Wen Yuan Gao
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China.
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Lai IL, You JF, Tsai WS, Hsu YJ, Chern YJ, Wu MY. Metformin increases pathological responses to rectal cancers with neoadjuvant chemoradiotherapy: a systematic review and meta-analysis. World J Surg Oncol 2023; 21:224. [PMID: 37491250 PMCID: PMC10369710 DOI: 10.1186/s12957-023-03087-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 06/28/2023] [Indexed: 07/27/2023] Open
Abstract
BACKGROUND To summarize the chemo-radio effect of metformin in rectal cancers with neoadjuvant chemoradiotherapy on pathological response, tumor regression grade (TRG), and T/N downstaging. METHODS PubMed, MEDLINE, Embase, and Cochrane Database of collected reviews were searched up to June 30, 2022. This study conducted systematic review and meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) sheet. Odds ratios (ORs) and confidence intervals (CIs) which calculated by random-effects models were displayed in forest plots. Newcastle-Ottawa scale was used to assess the risk of bias of the observational cohort studies. RESULTS This systematic review and meta-analysis comprised eight cohorts out of seven studies, with 2294 patients in total. We performed two-way comparison for metformin in diabetic patients vs (1) non-metformin drugs in diabetic patients and (2) nondiabetic patients. In diabetes patient studies, the metformin group had a significantly increased pathological response on TRG (OR: 3.28, CI: 2.01-5.35, I2 = 0%, p < 0.001) and T downstaging (OR: 2.14, CI: 1.24-3.67, I2 = 14%, p = 0.006) in comparison with a non-metformin group. When compared with nondiabetic patients, the pathological response on TRG (OR: 2.67, CI: 1.65-4.32, I2 = 43%, p < 0.001) and T downstaging (OR: 1.96, CI: 1.04-3.71, I2 = 66%, p = 0.04) were also higher in metformin group. The limitation was that no randomized controlled trials were available based on current literature review. Small sample sizes for diabetic metformin or non-metformin users in rectal cancer patients reduced the power of the study. CONCLUSIONS For patients with rectal cancer and treated with neoadjuvant chemoradiotherapy, metformin administration in diabetic patients increased the pathological response on tumor-regression grade and T downstaging. Further well-designed, high-quality randomized controlled trials are required to reveal the actual effect of metformin.
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Affiliation(s)
- I-Li Lai
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Guei-Shan District, Linkou Branch, No. 5, Fu-Hsing Street, Taoyuan City, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, No. 259, Wenhua 1St Rd, Guei-Shan District, Taoyuan City, Taiwan
- Department of SurgeryTen-Chen Medical GroupZhongli Dist., Zhong-Li Metropolitan Hospital, Yanping Rd, No. 155, Taoyuan City, Taiwan
| | - Jeng-Fu You
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Guei-Shan District, Linkou Branch, No. 5, Fu-Hsing Street, Taoyuan City, Taiwan
| | - Wen-Sy Tsai
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Guei-Shan District, Linkou Branch, No. 5, Fu-Hsing Street, Taoyuan City, Taiwan
| | - Yu-Jen Hsu
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Guei-Shan District, Linkou Branch, No. 5, Fu-Hsing Street, Taoyuan City, Taiwan
| | - Yih-Jong Chern
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Guei-Shan District, Linkou Branch, No. 5, Fu-Hsing Street, Taoyuan City, Taiwan
| | - Ming-Ying Wu
- Department of Dermatology, Chang Gung Memorial Hospital, Guei-Shan District, Linkou Branch, No. 5, Fu-Hsing Street, Taoyuan City, Taiwan.
- Institute of Epidemiology and Preventive Medicine, Zhongzheng Dist., National Taiwan University, Xuzhou Rd, No. 17, Taipei City, Taiwan.
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Singh AK, Amar I, Ramadasan H, Kappagantula KS, Chavali S. Proteins with amino acid repeats constitute a rapidly evolvable and human-specific essentialome. Cell Rep 2023; 42:112811. [PMID: 37453061 DOI: 10.1016/j.celrep.2023.112811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 05/30/2023] [Accepted: 06/29/2023] [Indexed: 07/18/2023] Open
Abstract
Protein products of essential genes, indispensable for organismal survival, are highly conserved and bring about fundamental functions. Interestingly, proteins that contain amino acid homorepeats that tend to evolve rapidly are enriched in eukaryotic essentialomes. Why are proteins with hypermutable homorepeats enriched in conserved and functionally vital essential proteins? We solve this functional versus evolutionary paradox by demonstrating that human essential proteins with homorepeats bring about crosstalk across biological processes through high interactability and have distinct regulatory functions affecting expansive global regulation. Importantly, essential proteins with homorepeats rapidly diverge with the amino acid substitutions frequently affecting functional sites, likely facilitating rapid adaptability. Strikingly, essential proteins with homorepeats influence human-specific embryonic and brain development, implying that the presence of homorepeats could contribute to the emergence of human-specific processes. Thus, we propose that homorepeat-containing essential proteins affecting species-specific traits can be potential intervention targets across pathologies, including cancers and neurological disorders.
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Affiliation(s)
- Anjali K Singh
- Department of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Tirupati 517507, Andhra Pradesh, India
| | - Ishita Amar
- Department of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Tirupati 517507, Andhra Pradesh, India
| | - Harikrishnan Ramadasan
- Department of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Tirupati 517507, Andhra Pradesh, India
| | - Keertana S Kappagantula
- Department of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Tirupati 517507, Andhra Pradesh, India
| | - Sreenivas Chavali
- Department of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Tirupati 517507, Andhra Pradesh, India.
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22
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Tanaka T, Lynch CF, Yu KJ, Morawski BM, Hsieh MC, Alverson G, Austin AA, Zeng Y, Engels EA. Pancreatic cancer among solid organ transplant recipients in the United States. J Cancer Res Clin Oncol 2023; 149:3325-3333. [PMID: 35932302 DOI: 10.1007/s00432-022-04227-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 07/18/2022] [Indexed: 12/01/2022]
Abstract
INTRODUCTION Pancreatic cancer (PC) in solid organ transplant (SOT) recipients is not well studied. Some PC cases may be incidentally detected during hepatobiliary imaging. METHODS We evaluated PC among 374,106 SOT recipients during 1995-2017 in the United States using linked data from the national transplant registry and multiple state/regional cancer registries. Standardized incidence ratios (SIRs) were used to compare PC risk in recipients to the general population. We used multivariate Poisson regression to identify independent risk factors for PC. We assessed survival after PC diagnosis using Kaplan-Meier curves and log-rank tests. RESULTS SOT recipients had elevated incidence for PC compared with the general population (SIR 1.40, 95% CI 1.29-1.52), and this increase was strongest in liver recipients (1.65, 1.41-1.92). Among all recipients, PC incidence was especially increased for cases arising in the head of the pancreas (SIR 1.50, 95% CI 1.34-1.68) and for cases diagnosed at localized stage (1.85, 1.37-2.44). Among SOT recipients, factors independently associated with increased incidence were consistent with those in general population including male sex, older age, non-O blood type, and history of diabetes. Additionally, compared to other organ recipients, liver transplant recipients had higher PC incidence (adjusted incidence rate ratio 1.28; 95% CI 1.06-1.54). Overall survival after PC diagnosis was poor (median 4 months) and similar between liver and other organ transplant recipients (p = 0.08). CONCLUSIONS PC incidence is elevated among SOT recipients, and more commonly diagnosed in liver transplant recipients perhaps related to incidental detection. However, survival is poor even in liver recipients, arguing against routine PC screening.
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Affiliation(s)
- Tomohiro Tanaka
- Division of Gastroenterology and Hepatology, The University of Iowa, Iowa City, IA, USA.
| | - Charles F Lynch
- Department of Epidemiology, The University of Iowa, Iowa City, IA, USA
| | - Kelly J Yu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Bozena M Morawski
- Cancer Data Registry of Idaho, Idaho Hospital Association, Boise, ID, USA
| | - Mei-Chin Hsieh
- Louisiana Tumor Registry and Epidemiology Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Georgetta Alverson
- Michigan Cancer Surveillance Program, Michigan Department of Health and Human Services, Lansing, MI, USA
| | - April A Austin
- New York State Cancer Registry, New York State Department of Health, Albany, NY, USA
| | - Yun Zeng
- North Dakota Statewide Cancer Registry, Grand Forks, ND, USA
| | - Eric A Engels
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
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23
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Dutta S, Shah RB, Singhal S, Dutta SB, Bansal S, Sinha S, Haque M. Metformin: A Review of Potential Mechanism and Therapeutic Utility Beyond Diabetes. Drug Des Devel Ther 2023; 17:1907-1932. [PMID: 37397787 PMCID: PMC10312383 DOI: 10.2147/dddt.s409373] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 06/10/2023] [Indexed: 07/04/2023] Open
Abstract
Metformin has been designated as one of the most crucial first-line therapeutic agents in the management of type 2 diabetes mellitus. Primarily being an antihyperglycemic agent, metformin also has a plethora of pleiotropic effects on various systems and processes. It acts majorly by activating AMPK (Adenosine Monophosphate-Activated Protein Kinase) in the cells and reducing glucose output from the liver. It also decreases advanced glycation end products and reactive oxygen species production in the endothelium apart from regulating the glucose and lipid metabolism in the cardiomyocytes, hence minimizing the cardiovascular risks. Its anticancer, antiproliferative and apoptosis-inducing effects on malignant cells might prove instrumental in the malignancy of organs like the breast, kidney, brain, ovary, lung, and endometrium. Preclinical studies have also shown some evidence of metformin's neuroprotective role in Parkinson's disease, Alzheimer's disease, multiple sclerosis and Huntington's disease. Metformin exerts its pleiotropic effects through varied pathways of intracellular signalling and exact mechanism in the majority of them remains yet to be clearly defined. This article has extensively reviewed the therapeutic benefits of metformin and the details of its mechanism for a molecule of boon in various conditions like diabetes, prediabetes, obesity, polycystic ovarian disease, metabolic derangement in HIV, various cancers and aging.
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Affiliation(s)
- Siddhartha Dutta
- Department of Pharmacology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Rima B Shah
- Department of Pharmacology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Shubha Singhal
- Department of Pharmacology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Sudeshna Banerjee Dutta
- Department of Medical Surgical Nursing, Shri Anand Institute of Nursing, Rajkot, Gujarat, 360005, India
| | - Sumit Bansal
- Department of Anaesthesiology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Susmita Sinha
- Department of Physiology, Khulna City Medical College and Hospital, Khulna, Bangladesh
| | - Mainul Haque
- Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kuala Lumpur, 57000, Malaysia
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24
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El-Tanani M, Nsairat H, Aljabali AA, Serrano-Aroca Á, Mishra V, Mishra Y, Naikoo GA, Alshaer W, Tambuwala MM. Role of mammalian target of rapamycin (mTOR) signalling in oncogenesis. Life Sci 2023; 323:121662. [PMID: 37028545 DOI: 10.1016/j.lfs.2023.121662] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/07/2023] [Accepted: 03/31/2023] [Indexed: 04/09/2023]
Abstract
The signalling system known as mammalian target of rapamycin (mTOR) is believed to be required for several biological activities involving cell proliferation. The serine-threonine kinase identified as mTOR recognises PI3K-AKT stress signals. It is well established in the scientific literature that the deregulation of the mTOR pathway plays a crucial role in cancer growth and advancement. This review focuses on the normal functions of mTOR as well as its abnormal roles in cancer development.
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Affiliation(s)
- Mohamed El-Tanani
- Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan; Institute of Cancer Therapeutics, University of Bradford, Bradford, West Yorkshire BD7 1DP, United Kingdom.
| | - Hamdi Nsairat
- Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan
| | - Alaa A Aljabali
- Department of Pharmaceutics and Pharmaceutical Technology, Yarmouk University, Irbid 21163, Jordan.
| | - Ángel Serrano-Aroca
- Biomaterials and Bioengineering Laboratory, Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia San Vicente Mártir, c/Guillem de Castro 94, 46001, Valencia, Spain.
| | - Vijay Mishra
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, 144411, Punjab, India
| | - Yachana Mishra
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, 144411, Punjab, India
| | - Gowhar A Naikoo
- Department of Mathematics and Sciences, College of Arts and Applied Sciences, Dhofar University, Salalah, PC 211, Oman.
| | - Walhan Alshaer
- Cell Therapy Center, the University of Jordan, Amman 11942, Jordan
| | - Murtaza M Tambuwala
- Lincoln Medical School, University of Lincoln, Brayford Pool Campus, Lincoln LN6 7TS, United Kingdom.
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Li J, Li B, Zhao R, Li G. Systematic analysis of the aberrances and functional implications of cuproptosis in cancer. iScience 2023; 26:106319. [PMID: 36950125 PMCID: PMC10025971 DOI: 10.1016/j.isci.2023.106319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/07/2022] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Cuproptosis is a novel form of cell death driven by a copper-dependent proteotoxic stress response whose comprehensive landscape in tumors remains unclear. Here, we comprehensively characterized cuproptosis-related genes (CRGs) across 33 cancers using multi-omic data from The Cancer Genome Atlas (TCGA), showing complicated and diverse results in different cancers. We also explored the relationships between CRGs and cancer metabolic patterns, pathway activity, and tumor microenvironment (TME), suggesting that they played critical roles in tumor progression and TME cell infiltration. We further established the cuproptosis potential index (CPI) to reveal the functional roles of cuproptosis, and characterized multi-omic molecular features associated with cuproptosis. In clinical applications, we performed a combined analysis of the sensitivity of CRGs and CPI to drug response and immunotherapy. This study provides a rich resource for understanding cuproptosis, offering a broad molecular perspective for future functional and therapeutic studies of multiple cancer pathways mediated by cuproptosis.
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Affiliation(s)
- Jiangbing Li
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021 Shandong, China
| | - Boyan Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012 Shandong, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250012 Shandong, China
| | - Rongrong Zhao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012 Shandong, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250012 Shandong, China
- Corresponding author
| | - Gang Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012 Shandong, China
- Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250012 Shandong, China
- Corresponding author
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26
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Andreo-López MC, Contreras-Bolívar V, Muñoz-Torres M, García-Fontana B, García-Fontana C. Influence of the Mediterranean Diet on Healthy Aging. Int J Mol Sci 2023; 24:4491. [PMID: 36901921 PMCID: PMC10003249 DOI: 10.3390/ijms24054491] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/18/2023] [Accepted: 02/21/2023] [Indexed: 03/02/2023] Open
Abstract
The life expectancy of the global population has increased. Aging is a natural physiological process that poses major challenges in an increasingly long-lived and frail population. Several molecular mechanisms are involved in aging. Likewise, the gut microbiota, which is influenced by environmental factors such as diet, plays a crucial role in the modulation of these mechanisms. The Mediterranean diet, as well as the components present in it, offer some proof of this. Achieving healthy aging should be focused on the promotion of healthy lifestyle habits that reduce the development of pathologies that are associated with aging, in order to increase the quality of life of the aging population. In this review we analyze the influence of the Mediterranean diet on the molecular pathways and the microbiota associated with more favorable aging patterns, as well as its possible role as an anti-aging treatment.
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Affiliation(s)
| | - Victoria Contreras-Bolívar
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, 18016 Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (Ibs. Granada), 18014 Granada, Spain
| | - Manuel Muñoz-Torres
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, 18016 Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (Ibs. Granada), 18014 Granada, Spain
- CIBER on Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, 18012 Granada, Spain
- Department of Medicine, University of Granada, 18016 Granada, Spain
| | - Beatriz García-Fontana
- Instituto de Investigación Biosanitaria de Granada (Ibs. Granada), 18014 Granada, Spain
- CIBER on Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, 18012 Granada, Spain
- Department of Cell Biology, University of Granada, 18016 Granada, Spain
| | - Cristina García-Fontana
- Endocrinology and Nutrition Unit, University Hospital Clínico San Cecilio, 18016 Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (Ibs. Granada), 18014 Granada, Spain
- CIBER on Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, 18012 Granada, Spain
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Identification and Validation of a Novel Glycolysis-Related Gene Signature for Predicting the Prognosis and Therapeutic Response in Triple-Negative Breast Cancer. Adv Ther 2023; 40:310-330. [PMID: 36316558 DOI: 10.1007/s12325-022-02330-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 09/21/2022] [Indexed: 01/21/2023]
Abstract
INTRODUCTION A high malignancy rate and poor prognosis are common problems with triple-negative breast cancer (TNBC). There is increasing evidence that glycolysis plays vital roles in tumorigenesis, tumor invasion, immune evasion, chemoresistance, and metastasis. However, a comprehensive analysis of the diagnostic and prognostic significance of glycolysis in TNBC is lacking. METHODS Transcriptomic and clinical data of TNBC patients were obtained from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) databases, respectively. Glycolysis-related genes (GRGs) were collected from the Molecular Signatures Database (MSigDB). Differential comparative analysis was performed to obtain the differentially expressed (DE)-GRGs associated with TNBC. Based on the DE-GRGs, a glycolysis-related risk signature was established using Least Absolute Shrinkage and Selector Operation (LASSO) and multivariable Cox regression analyses. The prognostic value, tumor microenvironment, mutation status, and chemotherapy response of different risk groups were analyzed. An independent cohort from the METABRIC database was used for external validation. Furthermore, the expression patterns of five genes derived from the prognostic model were validated by quantitative real-time polymerase chain reaction (RT-qPCR). RESULTS The glycolysis-related prognostic signature included five genes (IFNG, ACSS2, IRS2, GFUS, and GAL3ST1) and predicted the prognosis of TNBC patients independent of clinical factors (p < 0.05). Patients were divided into high- and low-risk groups based on the median risk score. Compared to low-risk TNBC patients, high-risk patients had significantly decreased overall survival (HR = 2.718, p < 0.001). Receiver operating characteristic and calibration curves demonstrated that the model had high performance in terms of predicting survival and risk stratification. The results remained consistent after external verification. Additionally, the tumor immune microenvironment significantly differed between the risk groups. Low-risk TNBC patients had a better immunotherapy response than high-risk patients. High-risk TNBC patients with a poor prognosis may benefit from targeted therapy. CONCLUSIONS This study developed a novel glycolysis and prognosis-related (GRP) signature based on GRGs to predict the prognosis of TNBC patients, and may aid clinical decision-making for these patients.
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28
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Huang Y, Zhai Y, Wu M, Chang C, Luo J, Hong D, Zhao Q, Dai Y, Liu J. Targeting mTOR Complex 2 in Castration-Resistant Prostate Cancer with Acquired Docetaxel Resistance. Drug Des Devel Ther 2022; 16:3817-3828. [PMID: 36388085 PMCID: PMC9642805 DOI: 10.2147/dddt.s376474] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 10/24/2022] [Indexed: 10/15/2023] Open
Abstract
PURPOSE Mammalian Target of rapamycin (mTOR) plays a central role in regulating cell growth, proliferation, and cell cycle. The key component of mTORC2 is highly expressed in docetaxel-resistant prostate cells. However, the underlying molecular effects on prostate cells remain unclear. METHODS A docetaxel-resistant human prostate cell line (PC-3/DTX) was constructed to investigate the role of mTORC2 in docetaxel resistance. The lentivirus was transfected into cells to knock down the expression of Rictor, and cell viability was measured by Cell Counting Kit 8 (CCK-8). Flow cytometry was used to analyze the cell cycle, and the changes in related signal cascades were assessed by immunohistochemistry (IHC) staining and Western blot. RESULTS Docetaxel showed the lowest IC50 (50% inhibitory concentration) in PC-3/DTX cells with sh-RNA. Decreased Rictor expression resulted in a larger proportion of arrested cells in the G0/G1 phase in PC-3/DTX cells. The IC50 values of the AZD8055 group were lower than in the Rapamycin group when treated with docetaxel again. Furthermore, a larger proportion of PC-3/DTX cells were arrested in the G0/G1 phase in the AZD8055 group compared to the Rapamycin group. The IHC results of the prostate cancer tissues from a CRPC patient revealed the over expression of Rictor only, while Raptor expression was unaffected. CONCLUSION We investigated the role of mTORC2 signaling on the acquired docetaxel -resistant PC-3 cells to identify potential methods for clinical treatment. MTORC2 expression is essential for docetaxel drug resistance of PC-3 cells. The mTORC1/2 inhibitor AZD8055 caused more significant disruption of mTORC2 kinase activity than the mTORC1 inhibitor Rapamycin, which lead to decreased docetaxel-mediated resistance. Therefore, reversing docetaxel resistance, may become a therapeutic option in the treatment of mCRPC patients.
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Affiliation(s)
- Yujie Huang
- Research Center for Clinical Pharmacy, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - You Zhai
- Research Center for Clinical Pharmacy, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Meijia Wu
- Research Center for Clinical Pharmacy, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Chengdong Chang
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Jindan Luo
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Dongsheng Hong
- Research Center for Clinical Pharmacy, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Qingwei Zhao
- Research Center for Clinical Pharmacy, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Yao Dai
- Department of Radiation Oncology, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Jian Liu
- Research Center for Clinical Pharmacy, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
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Itohara K, Yano I, Nakagawa S, Sugimoto M, Hirai M, Yonezawa A, Imai S, Nakagawa T, Hira D, Ito T, Hata K, Hatano E, Terada T, Matsubara K. Population pharmacokinetics of everolimus in adult liver transplant patients: Comparison to tacrolimus disposition and extrapolation to pediatrics. Clin Transl Sci 2022; 15:2652-2662. [PMID: 36004935 PMCID: PMC9652441 DOI: 10.1111/cts.13389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 07/14/2022] [Accepted: 08/05/2022] [Indexed: 01/25/2023] Open
Abstract
Everolimus has recently been used to prevent graft rejection in liver transplantation and reduces the incidence of kidney dysfunction caused by calcineurin inhibitors. In this study, a population pharmacokinetic analysis was conducted to improve the individualization of everolimus therapy. Japanese post-liver transplant patients whose blood everolimus concentrations were measured between March 2018 and December 2020 were included in this study. A nonlinear mixed-effect modeling program was used to explore covariates that affect everolimus pharmacokinetics. Individual everolimus pharmacokinetic parameters estimated by the post-hoc Bayesian analysis using the final model were compared with the tacrolimus dose per trough concentration (D/C) ratio in each patient. The final model was extrapolated to pediatric liver transplant patients for external evaluation. A total of 937 concentrations from 87 adult patients were used in the model-building process. Everolimus clearance was significantly affected by the estimated glomerular filtration rate, concomitant use of fluconazole, sex, as well as total daily dose of everolimus (TDM effect). The estimated individual apparent clearance of everolimus by the post-hoc Bayesian analysis was moderately correlated with the D/C ratio of tacrolimus in each patient (R2 = 0.330, p < 0.0001). The estimation accuracy in pediatric patients was considerably high, except for one infant out of 13 patients. In conclusion, population pharmacokinetic analysis clarified several significant covariates for everolimus pharmacokinetics in liver transplant patients. Everolimus pharmacokinetics moderately correlated with tacrolimus pharmacokinetics and could be extrapolated from adult to pediatric patients by body size correction, except for infants.
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Affiliation(s)
- Kotaro Itohara
- Department of Clinical Pharmacology and TherapeuticsKyoto University HospitalKyotoJapan
| | - Ikuko Yano
- Department of Clinical Pharmacology and TherapeuticsKyoto University HospitalKyotoJapan,Department of PharmacyKobe University HospitalKobeJapan
| | - Shunsaku Nakagawa
- Department of Clinical Pharmacology and TherapeuticsKyoto University HospitalKyotoJapan
| | - Mitsuhiro Sugimoto
- Department of Clinical Pharmacology and TherapeuticsKyoto University HospitalKyotoJapan
| | - Machiko Hirai
- Department of Clinical Pharmacology and TherapeuticsKyoto University HospitalKyotoJapan
| | - Atsushi Yonezawa
- Department of Clinical Pharmacology and TherapeuticsKyoto University HospitalKyotoJapan,Graduate School of Pharmaceutical SciencesKyoto UniversityKyotoJapan
| | - Satoshi Imai
- Department of Clinical Pharmacology and TherapeuticsKyoto University HospitalKyotoJapan
| | - Takayuki Nakagawa
- Department of Clinical Pharmacology and TherapeuticsKyoto University HospitalKyotoJapan
| | - Daiki Hira
- Department of Clinical Pharmacology and TherapeuticsKyoto University HospitalKyotoJapan
| | - Takashi Ito
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Koichiro Hata
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Etsuro Hatano
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Tomohiro Terada
- Department of Clinical Pharmacology and TherapeuticsKyoto University HospitalKyotoJapan
| | - Kazuo Matsubara
- Department of Clinical Pharmacology and TherapeuticsKyoto University HospitalKyotoJapan,Department of PharmacyWakayama Medical University HospitalWakayamaJapan
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McRitchie BR, Akkaya B. Exhaust the exhausters: Targeting regulatory T cells in the tumor microenvironment. Front Immunol 2022; 13:940052. [PMID: 36248808 PMCID: PMC9562032 DOI: 10.3389/fimmu.2022.940052] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 09/14/2022] [Indexed: 12/14/2022] Open
Abstract
The concept of cancer immunotherapy has gained immense momentum over the recent years. The advancements in checkpoint blockade have led to a notable progress in treating a plethora of cancer types. However, these approaches also appear to have stalled due to factors such as individuals' genetic make-up, resistant tumor sub-types and immune related adverse events (irAE). While the major focus of immunotherapies has largely been alleviating the cell-intrinsic defects of CD8+ T cells in the tumor microenvironment (TME), amending the relationship between tumor specific CD4+ T cells and CD8+ T cells has started driving attention as well. A major roadblock to improve the cross-talk between CD4+ T cells and CD8+ T cells is the immune suppressive action of tumor infiltrating T regulatory (Treg) cells. Despite their indispensable in protecting tissues against autoimmune threats, Tregs have also been under scrutiny for helping tumors thrive. This review addresses how Tregs establish themselves at the TME and suppress anti-tumor immunity. Particularly, we delve into factors that promote Treg migration into tumor tissue and discuss the unique cellular and humoral composition of TME that aids survival, differentiation and function of intratumoral Tregs. Furthermore, we summarize the potential suppression mechanisms used by intratumoral Tregs and discuss ways to target those to ultimately guide new immunotherapies.
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Affiliation(s)
- Bayley R. McRitchie
- Department of Neurology, The College of Medicine, The Ohio State University, Columbus, OH, United States
- Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Billur Akkaya
- Department of Neurology, The College of Medicine, The Ohio State University, Columbus, OH, United States
- Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
- Department of Microbial Infection and Immunity, The College of Medicine, The Ohio State University, Columbus, OH, United States
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Morawe MP, Liao F, Amberg W, van Bergeijk J, Chang R, Gulino M, Hamilton C, Hoft C, Lumpkin C, Mastis B, McGlame E, Nuber J, Plaas C, Ravikumar B, Roy K, Schanzenbächer M, Tierno J, Lakics V, Dellovade T, Townsend M. Pharmacological mTOR-inhibition facilitates clearance of AD-related tau aggregates in the mouse brain. Eur J Pharmacol 2022; 934:175301. [DOI: 10.1016/j.ejphar.2022.175301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 09/20/2022] [Accepted: 09/22/2022] [Indexed: 11/03/2022]
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Agarwal P, Mohamed A. Systemic Therapy of Advanced Well-differentiated Small Bowel Neuroendocrine Tumors Progressive on Somatostatin Analogues. Curr Treat Options Oncol 2022; 23:1233-1246. [PMID: 35939200 DOI: 10.1007/s11864-022-00998-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/03/2022] [Indexed: 11/30/2022]
Abstract
OPINION STATEMENT Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors whose management requires a nuanced and multi-disciplinary approach in order to control symptoms, halt tumor growth, and improve survival outcomes. Of late, the treatment landscape of NENs has advanced considerably as a result of several pivotal clinical trials, which have established somatostatin analogues as first-line therapy for advanced, metastatic, well-differentiated neuroendocrine tumors (NETs). However, an evolving classification system as well as an increased understanding of distinct clinical, molecular, and biologic features contribute to complexity in management. In particular, there remains limited randomized prospective data in the somatostatin analogue (SSA)-refractory setting for patients with primary tumors that originate in the small bowel. For well-differentiated small bowel neuroendocrine tumors (SBNETs), treatment beyond SSAs includes radionuclide therapy, targeted agents, liver-directed therapy, and to a lesser extent, cytotoxic chemotherapy. In the current era, selection of these agents is largely based on expert opinion in the context of patient and tumor characteristics without definitive data on the preferred order of agents to administer. In this review, we aim to describe the treatment landscape of metastatic SBNETs beyond SSAs and provide an overview of novel treatments which are currently under clinical evaluation.
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Affiliation(s)
- Parul Agarwal
- Hematology/Oncology, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, PCAM 10 South Pavilion, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA
| | - Amr Mohamed
- Department of Medical Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University, 11100 Euclid Avenue, Lakeside, Cleveland, OH, 44106, USA.
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33
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Sridhar J, Komati R, Kumar S. Targeting RPS6K1 for Refractory Breast Cancer Therapy. Breast Cancer 2022. [DOI: 10.36255/exon-publications-breast-cancer-rps6k1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Ding Z, Shen H, Xu K, Wu Y, Wang S, Yi F, Wang D, Liu Y. Comprehensive Analysis of mTORC1 Signaling Pathway–Related Genes in the Prognosis of HNSCC and the Response to Chemotherapy and Immunotherapy. Front Mol Biosci 2022; 9:792482. [PMID: 35573741 PMCID: PMC9100579 DOI: 10.3389/fmolb.2022.792482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 03/14/2022] [Indexed: 12/24/2022] Open
Abstract
Objective: The mammalian target of the rapamycin complex 1 (mTORC1) signaling pathway has emerged as a crucial player in the oncogenesis and development of head and neck squamous cell carcinoma (HNSCC), however, to date, no relevant gene signature has been identified. Therefore, we aimed to construct a novel gene signature based on the mTORC1 pathway for predicting the outcomes of patients with HNSCC and their response to treatment. Methods: The gene expression and clinical data were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The key prognostic genes associated with the mTORC1 pathway were screened by univariate Cox regression analyses. A prognostic signature was then established based on significant factors identified in the multivariate Cox regression analysis. The performance of the multigene signature was evaluated by the Kaplan–Meier (K–M) survival analysis and receiver operating characteristic (ROC) analysis. Based on the median risk score, patients were categorized into high- and low-risk groups. Subsequently, a hybrid prognostic nomogram was constructed and estimated by a calibration plot and decision curve analysis. Furthermore, immune cell infiltration and therapeutic responses were compared between the two risk groups. Finally, we measured the expression levels of seven genes by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). Results: The mTORC1 pathway–based signature was constructed using the seven identified genes (SEC11A, CYB5B, HPRT1, SLC2A3, SC5D, CORO1A, and PIK3R3). Patients in the high-risk group exhibited a lower overall survival (OS) rate than those in the low-risk group in both datasets. Through the univariate and multivariate Cox regression analyses, this gene signature was confirmed to be an independent prognostic risk factor for HNSCC. The constructed nomogram based on age, American Joint Committee on Cancer (AJCC) stage, and the risk score exhibited satisfactory performance in predicting the OS. In addition, immune cell infiltration and chemotherapeutic and immunotherapeutic responses differed significantly between the two risk groups. The expression levels of SEC11A and CYB5B were higher in HNSCC tissues than in normal tissues. Conclusion: Our study established and verified an mTORC1 signaling pathway–related gene signature that could be used as a novel prognostic factor for HNSCC.
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Affiliation(s)
- Zhao Ding
- Department of Otorhinolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Medical University, Hefei, China
- Graduate School of Anhui Medical University, Hefei, China
| | - Hailong Shen
- Department of Otorhinolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Medical University, Hefei, China
- Graduate School of Anhui Medical University, Hefei, China
| | - Ke Xu
- Department of Otorhinolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Medical University, Hefei, China
- Graduate School of Anhui Medical University, Hefei, China
| | - Yu Wu
- Department of Otorhinolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Otolaryngology, General Hospital of Anhui Wanbei Coal Power Group, Suzhou, China
| | - Shuhao Wang
- Department of Otorhinolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Medical University, Hefei, China
- Graduate School of Anhui Medical University, Hefei, China
| | - Fangzheng Yi
- Department of Otorhinolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Anhui Medical University, Hefei, China
- Graduate School of Anhui Medical University, Hefei, China
| | - Daming Wang
- Department of Otorhinolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yehai Liu
- Department of Otorhinolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: Yehai Liu,
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35
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Combined Targeting of AKT and mTOR Inhibits Tumor Formation of EpCAM+ and CD90+ Human Hepatocellular Carcinoma Cells in an Orthotopic Mouse Model. Cancers (Basel) 2022; 14:cancers14081882. [PMID: 35454789 PMCID: PMC9024696 DOI: 10.3390/cancers14081882] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/05/2022] [Accepted: 04/06/2022] [Indexed: 12/12/2022] Open
Abstract
The epithelial cell adhesion molecule (EpCAM) and Thy-1 cell surface antigen (CD90) have been implicated as cancer stem cell (CSC) markers in hepatocellular carcinoma (HCC). Expression of EpCAM and CD90 on HCC cells is associated with increased tumorigenicity, metastasis and poor prognosis. In this study, we demonstrate that combined treatment with AKT and mTOR inhibitors—i.e., MK2206 and RAD001—results in a synergistic reduction in proliferation of EpCAM+ and CD90+ HCC cells cultured either as adherent cells or as tumoroids in vitro. In addition, tumor growth was reduced by combined treatment with AKT and mTOR inhibitors in an orthotopic xenograft mouse model of an EpCAM+ HCC cell line (Huh7) and primary patient-derived EpCAM+ HCC cells (HCC1) as well as a CD90+ HCC-related cell line (SK-HEP1) in vivo. However, during AKT/mTOR treatment, outgrowth of therapy-resistant tumors was observed in all mice analyzed within a few weeks. Resistance was associated in most cases with restoration of AKT signaling in the tumors, intrahepatic metastases and distant metastases. In addition, an upregulation of the p38 MAPK pathway was identified in the AKT/mTOR inhibitor-resistant tumor cells by kinome profiling. The development of resistant cells during AKT/mTOR therapy was further analyzed by red-green-blue (RGB) marking of HCC cells, which revealed an outgrowth of a large number of Huh7 cells over a period of 6 months. In summary, our data demonstrate that combined treatment with AKT and mTOR inhibitors exhibits synergistic effects on proliferation of EpCAM+ as well as CD90+ HCC cells in vitro. However, the fast development of large numbers of resistant clones under AKT/mTOR therapy observed in vitro and in the orthotopic xenotransplantation mouse model in vivo strongly suggests that this therapy alone will not be sufficient to eliminate EpCAM+ or CD90+ cancer stem cells from HCC patients.
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36
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N 7-methylguanosine tRNA modification promotes esophageal squamous cell carcinoma tumorigenesis via the RPTOR/ULK1/autophagy axis. Nat Commun 2022; 13:1478. [PMID: 35304469 PMCID: PMC8933395 DOI: 10.1038/s41467-022-29125-7] [Citation(s) in RCA: 107] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 02/25/2022] [Indexed: 12/24/2022] Open
Abstract
Mis-regulated RNA modifications promote the processing and translation of oncogenic mRNAs to facilitate cancer progression, while the molecular mechanisms remain unclear. Here we reveal that tRNA m7G methyltransferase complex proteins METTL1 and WDR4 are significantly up-regulated in esophageal squamous cell carcinoma (ESCC) tissues and associated with poor ESCC prognosis. In addition, METTL1 and WDR4 promote ESCC progression via the tRNA m7G methyltransferase activity in vitro and in vivo. Mechanistically, METTL1 or WDR4 knockdown leads to decreased expression of m7G-modified tRNAs and reduces the translation of a subset of oncogenic transcripts enriched in RPTOR/ULK1/autophagy pathway. Furthermore, ESCC models using Mettl1 conditional knockout and knockin mice uncover the essential function of METTL1 in promoting ESCC tumorigenesis in vivo. Our study demonstrates the important oncogenic function of mis-regulated tRNA m7G modification in ESCC, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for ESCC treatment. Deregulation of METTL1-mediated N7- methylguanosine tRNA modification can promote oncogenesis. Here, the authors report that this modification regulates the translation of proteins in both the mTOR and negative regulators of autophagy pathways, resulting in the progression of esophageal squamous cell carcinoma.
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Correlation of nuclear pIGF-1R/IGF-1R and YAP/TAZ in a tissue microarray with outcomes in osteosarcoma patients. Oncotarget 2022; 13:521-533. [PMID: 35284040 PMCID: PMC8906536 DOI: 10.18632/oncotarget.28215] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 02/24/2022] [Indexed: 11/25/2022] Open
Abstract
Osteosarcoma (OS) is a genetically diverse bone cancer that lacks a consistent targetable mutation. Recent studies suggest the IGF/PI3K/mTOR pathway and YAP/TAZ paralogs regulate cell fate and proliferation in response to biomechanical cues within the tumor microenvironment. How this occurs and their implication upon osteosarcoma survival, remains poorly understood. Here, we show that IGF-1R can translocate into the nucleus, where it may act as part of a transcription factor complex. To explore the relationship between YAP/TAZ and total and nuclear phosphorylated IGF-1R (pIGF-1R), we evaluated sequential tumor sections from a 37-patient tissue microarray by confocal microscopy. Next, we examined the relationship between stained markers, clinical disease characteristics, and patient outcomes. The nuclear to cytoplasmic ratios (N:C ratio) of YAP and TAZ strongly correlated with nuclear pIGF-1R (r = 0.522, p = 0.001 for each pair). Kaplan-Meier analyses indicated that nuclear pIGF-1R predicted poor overall survival, a finding confirmed in the Cox proportional hazards model. Though additional investigation in a larger prospective study will be required to validate the prognostic accuracy of these markers, our results may have broad implications for the new class of YAP, TAZ, AXL, or TEAD inhibitors that have reached early phase clinical trials this year.
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Wang T, Long K, Zhou Y, Jiang X, Liu J, Fong JH, Wong AS, Ng WL, Wang W. Optochemical Control of mTOR Signaling and mTOR-Dependent Autophagy. ACS Pharmacol Transl Sci 2022; 5:149-155. [PMID: 35311017 PMCID: PMC8922298 DOI: 10.1021/acsptsci.1c00230] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Indexed: 11/29/2022]
Abstract
As an important regulator of cell metabolism, proliferation, and survival, mTOR (mammalian target of rapamycin) signaling provides both a potential target for cancer treatment and a research tool for investigation of cell metabolism. One inhibitor for both mTORC1 and mTORC2 pathways, OSI-027, exhibited robust anticancer efficacy but induced side effects. Herein, we designed a photoactivatable OSI-027 prodrug, which allowed the release of OSI-027 after light irradiation to inhibit the mTOR signaling pathway, triggering autophagy and leading to cell death. This photoactivatable prodrug can provide novel strategies for mTOR-targeting cancer therapy and act as a new tool for investigating mTOR signaling and its related biological processes.
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Affiliation(s)
- Tianyi Wang
- State
Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China
- Department
of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Dr.
Li Dak-Sum Research Centre, The University
of Hong Kong, Hong Kong 0000, China
| | - Kaiqi Long
- State
Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China
- Department
of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Dr.
Li Dak-Sum Research Centre, The University
of Hong Kong, Hong Kong 0000, China
| | - Yang Zhou
- State
Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China
- Department
of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Dr.
Li Dak-Sum Research Centre, The University
of Hong Kong, Hong Kong 0000, China
| | - Xiaoding Jiang
- School
of Pharmacy, Faculty of Medicine, The Chinese
University of Hong Kong, Hong Kong, China
| | - Jinzhao Liu
- Dr.
Li Dak-Sum Research Centre, The University
of Hong Kong, Hong Kong 0000, China
| | - John H.C. Fong
- Laboratory
of Combinatorial Genetics and Synthetic Biology, School of Biomedical
Sciences, The University of Hong Kong, Hong Kong China
| | - Alan S.L. Wong
- Laboratory
of Combinatorial Genetics and Synthetic Biology, School of Biomedical
Sciences, The University of Hong Kong, Hong Kong China
- Department
of Electrical and Electronic Engineering, The University of Hong Kong, Hong
Kong, China
| | - Wai-Lung Ng
- School
of Pharmacy, Faculty of Medicine, The Chinese
University of Hong Kong, Hong Kong, China
| | - Weiping Wang
- State
Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China
- Department
of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Dr.
Li Dak-Sum Research Centre, The University
of Hong Kong, Hong Kong 0000, China
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Yang R, Li Y, Wang H, Qin T, Yin X, Ma X. Therapeutic progress and challenges for triple negative breast cancer: targeted therapy and immunotherapy. MOLECULAR BIOMEDICINE 2022; 3:8. [PMID: 35243562 PMCID: PMC8894518 DOI: 10.1186/s43556-022-00071-6] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 02/09/2022] [Indexed: 02/08/2023] Open
Abstract
Triple negative breast cancer (TNBC) is a subtype of breast cancer, with estrogen receptor, human epidermal growth factor receptor 2 and progesterone receptor negative. TNBC is characterized by high heterogeneity, high rates of metastasis, poor prognosis, and lack of therapeutic targets. Now the treatment of TNBC is still based on surgery and chemotherapy, which is effective only in initial stage but almost useless in advanced stage. And due to the lack of hormone target, hormonal therapies have little beneficial effects. In recent years, signaling pathways and receptor-specific targets have been reported to be effective in TNBC patients under specific clinical conditions. Now targeted therapies have been approved for many other cancers and even other subtypes of breast cancer, but treatment options for TNBC are still limited. Most of TNBC patients showed no response, which may be related to the heterogeneity of TNBC, therefore more effective treatments and predictive biomarkers are needed. In the present review, we summarize potential treatment opinions for TNBC based on the dysregulated receptors and signaling pathways, which play a significant role in multiple stages of TNBC development. We also focus on the application of immunotherapy in TNBC, and summarize the preclinical and clinical trials of therapy for patients with TNBC. We hope to accelerate the research and development of new drugs for TNBC by understanding the relevant mechanisms, and to improve survival.
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Affiliation(s)
- Ruoning Yang
- Department of Biotherapy, State Key Laboratory of Biotherapy,Cancer Center, West China Hospital, 37 Guoxue Alley, Chengdu, 610041, PR, China.,Department of Breast Surgery, Clinical Research Center for Breast, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yueyi Li
- Department of Biotherapy, State Key Laboratory of Biotherapy,Cancer Center, West China Hospital, 37 Guoxue Alley, Chengdu, 610041, PR, China
| | - Hang Wang
- Department of Biotherapy, State Key Laboratory of Biotherapy,Cancer Center, West China Hospital, 37 Guoxue Alley, Chengdu, 610041, PR, China
| | - Taolin Qin
- West China Hospital, West China Medical School Sichuan University, Chengdu, PR, China
| | - Xiaomeng Yin
- Department of Biotherapy, State Key Laboratory of Biotherapy,Cancer Center, West China Hospital, 37 Guoxue Alley, Chengdu, 610041, PR, China
| | - Xuelei Ma
- Department of Biotherapy, State Key Laboratory of Biotherapy,Cancer Center, West China Hospital, 37 Guoxue Alley, Chengdu, 610041, PR, China.
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40
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Levy S, Verbeek WH, Eskens FA, van den Berg JG, de Groot DJA, van Leerdam ME, Tesselaar ME. First-line everolimus and cisplatin in patients with advanced extrapulmonary neuroendocrine carcinoma: a nationwide phase 2 single-arm clinical trial. Ther Adv Med Oncol 2022; 14:17588359221077088. [PMID: 35251315 PMCID: PMC8891910 DOI: 10.1177/17588359221077088] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 01/12/2022] [Indexed: 11/23/2022] Open
Abstract
Background: Extrapulmonary neuroendocrine carcinoma (EP-NEC) are an aggressive subgroup of neuroendocrine neoplasms (NEN). Advanced EP-NEC is generally treated with platinum-based cytotoxic regimens, but progressive disease occurs rapidly, resulting in a poor prognosis. Genetic alterations in the mammalian target for rapamycin (mTOR) pathway have been identified in NEN, providing a rationale for treatment with the mTOR-inhibitor everolimus. Methods: A prospective phase 2 single-arm study included patients with advanced EP-NEC from three Dutch NEN expertise centres between March 2016 and January 2020. Treatment consisted of cisplatin 75 mg/m2 every 3 weeks in combination with daily everolimus 7.5 mg for a maximum of six cycles, followed by maintenance everolimus until disease progression. Primary endpoint was disease control rate (DCR), defined as the sum of overall response rate (ORR) plus the rate of stable disease according to RECIST 1.1, assessed at 9-week intervals. Toxicity was evaluated according to CTCAE version 5.0. Results: Thirty-nine patients, with a median age of 64 years (range: 28–74), of whom 20 (51%) were male, were enrolled. DCR was 82.1% (95% confidence interval (CI): 66.4–92.4), with an ORR of 58.9% (CI: 42.1–74.4). Median duration of response was 6.4 (CI: 5.8–7.0) months and median progression-free survival was 6.0 (CI: 4.3–7.8) months. Three patients (8%) had durable responses lasting > 12 months. Median overall survival was 8.7 (CI: 7.8–9.6) months. Most common grade 3/4 toxicities were haematological (36%) and renal (21%). Conclusion: Everolimus in combination with cisplatin is an effective first-line treatment option for advanced EP-NEC, especially in highly selected patients. Trial registration: Clinicaltrials.gov, NCT02695459, https://clinicaltrials.gov/ct2/show/NCT02695459.
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Affiliation(s)
- Sonja Levy
- Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Wieke H.M. Verbeek
- Department of Gastroenterological Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Ferry A.L.M. Eskens
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - José G. van den Berg
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Derk Jan A. de Groot
- Department of Medical Oncology, University Medical Centre Groningen, Groningen, The Netherlands
| | - Monique E. van Leerdam
- Department of Gastroenterological Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Margot E.T. Tesselaar
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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Imamura R, Tanaka R, Taniguchi A, Nakazawa S, Kato T, Yamanaka K, Namba-Hamano T, Kakuta Y, Abe T, Tsutahara K, Takao T, Kishikawa H, Nonomura N. Everolimus Reduces Cancer Incidence and Improves Patient and Graft Survival Rates after Kidney Transplantation: A Multi-Center Study. J Clin Med 2022; 11:249. [PMID: 35011990 PMCID: PMC8746009 DOI: 10.3390/jcm11010249] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 12/27/2021] [Accepted: 12/29/2021] [Indexed: 02/05/2023] Open
Abstract
Kidney transplantation can prevent renal failure and associated complications in patients with end-stage renal disease. Despite the good quality of life, de novo cancers after kidney transplantation are a major complication impacting survival and there is an urgent need to establish immunosuppressive protocols to prevent de novo cancers. We conducted a multi-center retrospective study of 2002 patients who underwent kidney transplantation between 1965 and 2020 to examine patient and graft survival rates and cumulative cancer incidence in the following groups categorized based on specific induction immunosuppressive therapies: group 1, antiproliferative agents and steroids; group 2, calcineurin inhibitors (CNIs), antiproliferative agents and steroids; group 3, CNIs, mycophenolate mofetil, and steroids; and group 4, mammalian target of rapamycin inhibitors including everolimus, CNIs, mycophenolate mofetil, and steroids. The patient and graft survival rates were significantly higher in groups 3 and 4. The cumulative cancer incidence rate significantly increased with the use of more potent immunosuppressants, and the time to develop cancer was shorter. Only one patient in group 4 developed de novo cancer. Potent immunosuppressants might improve graft survival rate while inducing de novo cancer after kidney transplantation. Our data also suggest that everolimus might suppress cancer development after kidney transplantation.
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Affiliation(s)
- Ryoichi Imamura
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; (R.T.); (A.T.); (S.N.); (T.K.); (K.Y.); (T.A.); (N.N.)
| | - Ryo Tanaka
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; (R.T.); (A.T.); (S.N.); (T.K.); (K.Y.); (T.A.); (N.N.)
| | - Ayumu Taniguchi
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; (R.T.); (A.T.); (S.N.); (T.K.); (K.Y.); (T.A.); (N.N.)
| | - Shigeaki Nakazawa
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; (R.T.); (A.T.); (S.N.); (T.K.); (K.Y.); (T.A.); (N.N.)
| | - Taigo Kato
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; (R.T.); (A.T.); (S.N.); (T.K.); (K.Y.); (T.A.); (N.N.)
| | - Kazuaki Yamanaka
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; (R.T.); (A.T.); (S.N.); (T.K.); (K.Y.); (T.A.); (N.N.)
| | - Tomoko Namba-Hamano
- Department of Nephrology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan;
| | - Yoichi Kakuta
- Osaka General Medical Center, Department of Urology, Osaka 558-8558, Japan; (Y.K.); (K.T.); (T.T.)
| | - Toyofumi Abe
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; (R.T.); (A.T.); (S.N.); (T.K.); (K.Y.); (T.A.); (N.N.)
| | - Koichi Tsutahara
- Osaka General Medical Center, Department of Urology, Osaka 558-8558, Japan; (Y.K.); (K.T.); (T.T.)
| | - Tetsuya Takao
- Osaka General Medical Center, Department of Urology, Osaka 558-8558, Japan; (Y.K.); (K.T.); (T.T.)
| | - Hidefumi Kishikawa
- Department of Urology, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya 662-0918, Japan;
| | - Norio Nonomura
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; (R.T.); (A.T.); (S.N.); (T.K.); (K.Y.); (T.A.); (N.N.)
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Afroz R, Tanvir EM, Tania M, Fu J, Kamal MA, Khan MA. LPS/TLR4 Pathways in Breast Cancer: Insights into Cell Signalling. Curr Med Chem 2022; 29:2274-2289. [PMID: 34382520 DOI: 10.2174/0929867328666210811145043] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 07/01/2021] [Accepted: 07/10/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Cancer cells are usually recognized as foreign particles by the immune cells. Mounting evidence suggest an important link between toll-like receptors (TLRs) and carcinogenesis. This review article focused on the role of TLRs, especially TLR4, in breast cancer. METHODS Research data on TLRs and cancer was explored in PubMed, Scopus, Google Scholar and reviewed. Although some pioneer works are referenced, papers published in the last ten years were mostly cited. RESULTS TLRs are widely investigated pattern recognition receptors (PRR), and TLR4 is the most studied TLRs, implicated with the occurrence of several types of cancers, including breast cancer. TLR4 activation occurs via the binding of its ligand lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria. Upon LPS binding, TLR4 dimerizes and recruits downstream signalling and/or adapter molecules, leading to gene expression related to cancer cell proliferation, survival, invasion, and metastasis. Although LPS/TLR4 signalling seems a single signal transduction pathway, the TLR4 activation results in the activation of multiple diverse intracellular networks with huge cellular responses in both immune and cancer cells. The role of TLR4 in the growth, invasion, and metastasis of breast cancer is attracting huge attention in oncology research. Several clinical and preclinical studies utilize both TLR4 agonists and antagonists as a treatment option for cancer therapy, either as monotherapy or adjuvants for vaccine development. CONCLUSION This review narrates the role of LPS/TLR4 signalling in breast cancer development and future prospects for targeting LPS/TLR4 axis in the treatment of breast cancer.
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Affiliation(s)
- Rizwana Afroz
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia
| | - E M Tanvir
- School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia
- Veterinary Drug Residue Analysis Division, Institute of Food and Radiation Biology, Atomic Energy Research Establishment, Bangladesh Atomic Energy Commission, Dhaka, Bangladesh
| | - Mousumi Tania
- Research Division, Nature Study Society of Bangladesh, Dhaka, Bangladesh
- Division of Molecular Cancer, Red Green Research Center, Dhaka, Bangladesh
| | - Junjiang Fu
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Mohammad Amjad Kamal
- King Fahd Medical Research Center, King Abdulaziz University, Jaddah, Saudi Arabia
| | - Md Asaduzzaman Khan
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China
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Synergistic effects of Rapamycin and Fluorouracil to treat a gastric tumor in a PTEN conditional deletion mouse model. Gastric Cancer 2022; 25:96-106. [PMID: 34370147 DOI: 10.1007/s10120-021-01229-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 08/03/2021] [Indexed: 02/07/2023]
Abstract
The tumor suppressor gene phosphatase and tensin homolog (PTEN) in PI3K/Akt/mTOR pathway is essential in inhibiting tumor growth and metastasis. However, whether the mutation of PTEN gene could induce tumorigenesis and impact the treatment of gastric cancer is still unclear. The purpose of the study was to investigate the combined treatment of gastric tumorigenesis using Rapamycin and Fluorouracil (5-Fu) through interfering with the Akt/mTOR pathway in a mouse model with PTEN conditional deletion. Three groups of mice were exposed for 5 days to Rapamycin and 5-Fu separately and together. The gene expression of the Akt/mTOR pathway, the protein expression of caspase-3 and p-Akt, p-S6K and p-4EBP1, and the pathological changes in stomachs were analyzed. Our study demonstrates that the conditional PTEN deletion in the cells of glandular stomach induces hyperplastic gastric tumors in mice. The combined Rapamycin administration with 5-Fu resulted in better outcomes than their separate administration for the treatment of gastric cancer by inhibiting the mTOR signal pathway. Our study indicates that Rapamycin has a synergistic interaction with chemotherapeutic 5-Fu, and demonstrates a potential therapeutic combination treatment on glandular stomach tumor with PTEN functional absence or aberrantly activated Akt/mTOR pathway. It provides important insights into the inhibition of the Akt/mTOR pathway in gastric cancer clinical therapy.
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Sanaei MJ, Baghery Saghchy Khorasani A, Pourbagheri-Sigaroodi A, Shahrokh S, Zali MR, Bashash D. The PI3K/Akt/mTOR axis in colorectal cancer: Oncogenic alterations, non-coding RNAs, therapeutic opportunities, and the emerging role of nanoparticles. J Cell Physiol 2021; 237:1720-1752. [PMID: 34897682 DOI: 10.1002/jcp.30655] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/02/2021] [Accepted: 11/24/2021] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of the deadliest human malignancies worldwide. Several molecular pathways have been demonstrated to be involved in the initiation and development of CRC which among them, the overactivation of the phosphatidyl-inositol 3-kinase (PI3K)/Akt/mTOR axis is of importance. The current review aims to unravel the mechanisms by which the PI3K/Akt/mTOR pathway affects CRC progression; and also, to summarize the original data obtained from international research laboratories on the oncogenic alterations and polymorphisms affecting this pathway in CRC. Besides, we provide a special focus on the regulatory role of noncoding RNAs targeting the PI3K/Akt/mTOR pathway in this malignancy. Questions on how this axis is involved in the inhibition of apoptosis, in the induction of drug resistance, and the angiogenesis, epithelial to mesenchymal transition, and metastasis are also responded. We also discussed the PI3K/Akt pathway-associated prognostic and predictive biomarkers in CRC. In addition, we provide a general overview of PI3K/Akt/mTOR pathway inhibition whether by chemical-based drugs or by natural-based medications in the context of CRC, either as monotherapy or in combination with other therapeutic agents; however, those treatments might have life-threatening side effects and toxicities. To the best of our knowledge, the current review is one of the first ones highlighting the emerging roles of nanotechnology to overcome challenges related to CRC therapy in the hope that providing a promising platform for the treatment of CRC.
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Affiliation(s)
- Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Shahrokh
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Shen C, Shyu DL, Xu M, Yang L, Webb A, Duan W, Williams TM. Deregulation of AKT-mTOR Signaling Contributes to Chemoradiation Resistance in Lung Squamous Cell Carcinoma. Mol Cancer Res 2021; 20:425-433. [PMID: 34810212 DOI: 10.1158/1541-7786.mcr-21-0272] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 08/31/2021] [Accepted: 11/17/2021] [Indexed: 11/16/2022]
Abstract
Lung squamous cell carcinoma (LUSC) accounts for one of three of non-small cell lung carcinoma (NSCLC) and 30% of LUSC patients present with locally advanced, unresectable/medically inoperable disease, who are commonly treated with definitive chemoradiation. However, disease relapse in the radiation fields occurs in one of three cases. We aim to explore the underlying molecular mechanisms of chemoradiation resistance of LUSC. Patient-derived xenograft (PDX) models of LUSC were established in immunodeficient mice, followed by treatment with cisplatin in combination with clinically relevant courses of ionizing radiation (20, 30, and 40 Gy). The recurrent tumors were extracted for functional proteomics using reverse phase protein analysis (RPPA). We found that phospho-AKT-S473, phospho-AKT-T308, phospho-S6-S235/6, and phospho-GSK3β-S9 were upregulated in the chemoradiation-resistant 20 Gy + cisplatin and 40 Gy + cisplatin tumors compared with those in the control tumors. Ingenuity pathway analysis of the RPPA data revealed that AKT-mTOR signaling was the most activated signaling pathway in the chemoradiation-resistant tumors. Similarly, elevated AKT-mTOR signaling was observed in stable 40 Gy and 60 Gy resistant HARA cell lines compared with the parental cell line. Accordingly, pharmacologic inhibition of mTOR kinase by Torin2 significantly sensitized LUSC cell lines to ionizing radiation. In conclusion, using chemoradiation-resistant PDX models coupled with RPPA proteomics analysis, we revealed that deregulation of AKT-mTOR signaling may contribute to the chemoradiation resistance of LUSC. IMPLICATIONS: Clonal selection of subpopulations with high AKT-mTOR signaling in heterogeneous tumors may contribute to relapse of LUSC after chemoradiation. mTOR kinase inhibitors may be promising radiosensitizing agents in upfront treatment to prevent acquired resistance.
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Affiliation(s)
- Changxian Shen
- Department of Radiation Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California. .,The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio
| | - Duan-Liang Shyu
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio
| | - Min Xu
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Linlin Yang
- Department of Radiation Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California.,The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio
| | - Amy Webb
- The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio
| | - Wenrui Duan
- Herbert Wertheim College of Medicine at the Florida International University, Miami, Florida
| | - Terence M Williams
- Department of Radiation Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California. .,The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio
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Shen C, He Y, Chen Q, Feng H, Williams TM, Lu Y, He Z. Narrative review of emerging roles for AKT-mTOR signaling in cancer radioimmunotherapy. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1596. [PMID: 34790802 PMCID: PMC8576660 DOI: 10.21037/atm-21-4544] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 09/27/2021] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To summarize the roles of AKT-mTOR signaling in the regulation of the DNA damage response and PD-L1 expression in cancer cells, and propose a novel strategy of targeting AKT-mTOR signaling in combination with radioimmunotherapy in the era of cancer immunotherapy. BACKGROUND Immunotherapy has greatly improved the clinical outcomes of many cancer patients and has changed the landscape of cancer patient management. However, only a small subgroup of cancer patients (~20-30%) benefit from immune checkpoint blockade-based immunotherapy. The current challenge is to find biomarkers to predict the response of patients to immunotherapy and strategies to sensitize patients to immunotherapy. METHODS Search and review the literature which were published in PUBMED from 2000-2021 with the key words mTOR, AKT, drug resistance, DNA damage response, immunotherapy, PD-L1, DNA repair, radioimmunotherapy. CONCLUSIONS More than 50% of cancer patients receive radiotherapy during their course of treatment. Radiotherapy has been shown to reduce the growth of locally irradiated tumors as well as metastatic non-irradiated tumors (abscopal effects) by affecting systemic immunity. Consistently, immunotherapy has been demonstrated to enhance radiotherapy with more than one hundred clinical trials of radiation in combination with immunotherapy (radioimmunotherapy) across cancer types. Nevertheless, current available data have shown limited efficacy of trials testing radioimmunotherapy. AKT-mTOR signaling is a major tumor growth-promoting pathway and is upregulated in most cancers. AKT-mTOR signaling is activated by growth factors as well as genotoxic stresses including radiotherapy. Importantly, recent advances have shown that AKT-mTOR is one of the main signaling pathways that regulate DNA damage repair as well as PD-L1 levels in cancers. These recent advances clearly suggest a novel cancer therapy strategy by targeting AKT-mTOR signaling in combination with radioimmunotherapy.
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Affiliation(s)
- Changxian Shen
- Department of Radiation Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - Yuqi He
- Monash School of Medicine, Monash University, Clayton, VIC, Australia
| | - Qiang Chen
- Department of Oncology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Haihua Feng
- Department of Radiation Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - Terence M. Williams
- Department of Radiation Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - Yuanzhi Lu
- Department of Clinical Pathology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Zhengfu He
- Department of Thoracic Surgery, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou, China
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Wang B, Zhang W, Zhang G, Kwong L, Lu H, Tan J, Sadek N, Xiao M, Zhang J, Labrie M, Randell S, Beroard A, Sugarman E, Rebecca VW, Wei Z, Lu Y, Mills GB, Field J, Villanueva J, Xu X, Herlyn M, Guo W. Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma. Oncogene 2021; 40:5590-5599. [PMID: 34304249 PMCID: PMC8445818 DOI: 10.1038/s41388-021-01911-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 06/14/2021] [Accepted: 06/17/2021] [Indexed: 12/30/2022]
Abstract
Targeting MAPK pathway using a combination of BRAF and MEK inhibitors is an efficient strategy to treat melanoma harboring BRAF-mutation. The development of acquired resistance is inevitable due to the signaling pathway rewiring. Combining western blotting, immunohistochemistry, and reverse phase protein array (RPPA), we aim to understanding the role of the mTORC1 signaling pathway, a center node of intracellular signaling network, in mediating drug resistance of BRAF-mutant melanoma to the combination of BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) therapy. The mTORC1 signaling pathway is initially suppressed by BRAFi and MEKi combination in melanoma but rebounds overtime after tumors acquire resistance to the combination therapy (CR) as assayed in cultured cells and PDX models. In vitro experiments showed that a subset of CR melanoma cells was sensitive to mTORC1 inhibition. The mTOR inhibitors, rapamycin and NVP-BEZ235, induced cell cycle arrest and apoptosis in CR cell lines. As a proof-of-principle, we demonstrated that rapamycin and NVP-BEZ235 treatment reduced tumor growth in CR xenograft models. Mechanistically, AKT or ERK contributes to the activation of mTORC1 in CR cells, depending on PTEN status of these cells. Our study reveals that mTOR activation is essential for drug resistance of melanoma to MAPK inhibitors, and provides insight into the rewiring of the signaling networks in CR melanoma.
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Affiliation(s)
- Beike Wang
- Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, USA
| | - Wei Zhang
- Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, USA
| | - Gao Zhang
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
- Department of Neurosurgery, The Preston Robert Tisch Brain Tumor Center and Department of Pathology, Duke University Medical Center, Durham, NC, USA
| | - Lawrence Kwong
- Department of Translation Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hezhe Lu
- Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Jiufeng Tan
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Norah Sadek
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Min Xiao
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Jie Zhang
- Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA
| | - Marilyne Labrie
- Department of Cell, Developmental and Cancer Biology, School of Medicine, and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Sergio Randell
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Aurelie Beroard
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Eric Sugarman
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Vito W Rebecca
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Zhi Wei
- Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA
| | - Yiling Lu
- Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Gordon B Mills
- Department of Cell, Developmental and Cancer Biology, School of Medicine, and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Jeffrey Field
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jessie Villanueva
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
| | - Xiaowei Xu
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Meenhard Herlyn
- Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
| | - Wei Guo
- Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, USA.
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Wang L, Sun J, Han J, Ma Z, Pan M, Du Z. MiR-181a Promotes Spermatogenesis by Targeting the S6K1 Pathway. Int J Stem Cells 2021; 14:341-350. [PMID: 33906981 PMCID: PMC8429941 DOI: 10.15283/ijsc21001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 02/11/2021] [Accepted: 03/15/2021] [Indexed: 12/31/2022] Open
Abstract
Approximately 15% of couples suffer from infertility worldwide, and male factors contribute to about 30% of total sterility cases. However, there is little progress in treatments due to the obscured understanding of underlying mechanisms. Recently microRNAs have emerged as a key player in the process of spermatogenesis. Expression profiling of miR-181a was carried out in murine testes and spermatocyte culture system. In vitro cellular and biochemical assays were used to examine the effect of miR-181a and identify its target S6K1, as well as elucidate the function with chemical inhibitor of S6K1. Human testis samples analysis was employed to validate the findings. miR-181a level was upregulated during mouse spermatogenesis and knockdown of miR-181a attenuated the cell proliferation and G1/S arrest and increased the level of S6K1, which was identified as a downstream target of miR-181a. Overexpression of S6K1 also led to growth arrest of spermatocytes while inhibitor of S6K1 rescued the miR-181a knockdown-mediated cell proliferation defect. In human testis samples of azoospermia patients, low level of miR-181a was correlated with defects in the spermatogenic process. miR-181a is identified as a new regulator and high level of miR-181a contributes to spermatogenesis via targeting S6K1.
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Affiliation(s)
- Lei Wang
- Reproductive Medical Center, Zaozhuang Maternal and Child Health Hospital, Zaozhuang, China
| | - Juan Sun
- Department of Gynaecology, Zaozhuang Maternal and Child Health Hospital, Zaozhuang, China
| | - Jin Han
- Reproductive Medical Center, Zaozhuang Maternal and Child Health Hospital, Zaozhuang, China
| | - Zhaowen Ma
- Reproductive Medical Center, Zaozhuang Maternal and Child Health Hospital, Zaozhuang, China
| | - Meiling Pan
- Reproductive Medical Center, Zaozhuang Maternal and Child Health Hospital, Zaozhuang, China
| | - Zhaojin Du
- Reproductive Medical Center, Qingdao Women and Children's Hospital, Qingdao University, Qingdao, China
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Bryan S, Witzel I, Borgmann K, Oliveira-Ferrer L. Molecular Mechanisms Associated with Brain Metastases in HER2-Positive and Triple Negative Breast Cancers. Cancers (Basel) 2021; 13:4137. [PMID: 34439289 PMCID: PMC8392331 DOI: 10.3390/cancers13164137] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/09/2021] [Accepted: 08/12/2021] [Indexed: 12/14/2022] Open
Abstract
Breast cancer (BC) is the most frequent cause of cancer-associated death for women worldwide, with deaths commonly resulting from metastatic spread to distant organs. Approximately 30% of metastatic BC patients develop brain metastases (BM), a currently incurable diagnosis. The influence of BC molecular subtype and gene expression on breast cancer brain metastasis (BCBM) development and patient prognosis is undeniable and is, therefore, an important focus point in the attempt to combat the disease. The HER2-positive and triple-negative molecular subtypes are associated with an increased risk of developing BCBM. Several genetic and molecular mechanisms linked to HER2-positive and triple-negative BC breast cancers appear to influence BCBM formation on several levels, including increased development of circulating tumor cells (CTCs), enhanced epithelial-mesenchymal transition (EMT), and migration of primary BC cells to the brain and/or through superior local invasiveness aided by cancer stem-like cells (CSCs). These specific BC characteristics, together with the ensuing developments at a clinical level, are presented in this review article, drawing a connection between research findings and related therapeutic strategies aimed at preventing BCBM formation and/or progression. Furthermore, we briefly address the critical limitations in our current understanding of this complex topic, highlighting potential focal points for future research.
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Affiliation(s)
- Sarah Bryan
- Department of Gynaecology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (S.B.); (I.W.)
| | - Isabell Witzel
- Department of Gynaecology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (S.B.); (I.W.)
| | - Kerstin Borgmann
- Center of Oncology, Laboratory of Radiobiology & Experimental Radiooncology, Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany;
| | - Leticia Oliveira-Ferrer
- Department of Gynaecology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (S.B.); (I.W.)
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Chen Y, Tsai HW, Tsai YH, Tseng SH. VS-5584, a PI3K/mTOR dual inhibitor, exerts antitumor effects on neuroblastomas in vitro and in vivo. J Pediatr Surg 2021; 56:1441-1448. [PMID: 33189297 DOI: 10.1016/j.jpedsurg.2020.10.033] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 10/15/2020] [Accepted: 10/30/2020] [Indexed: 01/22/2023]
Abstract
BACKGROUND The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is closely related to oncogenesis. PI3K/mTOR inhibitors are considered capable of counteracting the feedback mechanisms within the pathway. In this study, we investigated the antitumor effects of VS-5584, an orally administered PI3K/mTOR dual inhibitor, on neuroblastomas. METHODS The effects of VS-5584 on proliferation, cell cycle distribution, and related signaling molecules were examined in neuroblastoma cells using the (3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide)-based colorimetric assay, flow cytometry, and western blotting, respectively. Nude mice were subcutaneously inoculated with human neuroblastoma cells, followed by VS-5584 treatment for two weeks. Tumor growth was tracked and tumor tissues were subjected to immunohistochemical investigations. RESULTS In neuroblastoma cells, VS-5584 significantly inhibited proliferation and induced G0/G1 cell cycle arrest. Additionally, VS-5584 decreased the expression of phospho-S6 kinase 1 (p-S6K1), p-retinoblastoma protein, p-cyclin-dependent kinase 2, and cyclin E1, and increased the expression of p21 and p27 in neuroblastoma cells. In mice, VS-5584 significantly suppressed tumor growth in neuroblastomas and downregulated the expression of p-mTOR and p-S6K1 in tumor tissues. CONCLUSIONS VS-5584 blocks the PI3K/mTOR pathway, induces a G0/G1 cell cycle arrest, and exerts antitumor effects on neuroblastomas both in vitro and in vivo.
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Affiliation(s)
- Yun Chen
- Department of Surgery, Far Eastern Memorial Hospital, Pan-Chiao, New Taipei, Taiwan; Graduate Institute of Medicine and Department of Chemical Engineering and Materials Science, Yuan Ze University, Chung-Li, Taoyuan, Taiwan
| | - Huang-Wen Tsai
- Department of Surgery, Far Eastern Memorial Hospital, Pan-Chiao, New Taipei, Taiwan
| | - Ya-Hui Tsai
- Department of Surgery, Far Eastern Memorial Hospital, Pan-Chiao, New Taipei, Taiwan; Graduate Institute of Medicine and Department of Chemical Engineering and Materials Science, Yuan Ze University, Chung-Li, Taoyuan, Taiwan.
| | - Sheng-Hong Tseng
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
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