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1
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Wu X, Yamashita K, Lou M, Matsumoto C, Zhang W, Baba H, Iwatsuki M. AT101 Suppresses Gastrointestinal Stromal Tumor Growth and Promotes Apoptosis via YAP/TAZ-CCND1 and FBXW7-MCL1 Axes. Ann Surg Oncol 2025:10.1245/s10434-025-17247-3. [PMID: 40148719 DOI: 10.1245/s10434-025-17247-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Accepted: 03/09/2025] [Indexed: 03/29/2025]
Abstract
BACKGROUND Imatinib (IM), a tyrosine kinase inhibitor (TKI), is the first-line treatment for patients with gastrointestinal stromal tumors (GISTs). However, its efficacy is limited due to acquired resistance induced by secondary KIT mutations in most patients with GIST. Furthermore, new challenges have emerged following the clarification that KIT-independent GISTs exhibit strong resistance to small molecule inhibitors targeting KIT/ platelet-derived growth factor receptor alpha (PDGFRA). Therefore, investigating the underlying therapeutic targets for imatinib-resistant GISTs is urgently necessitated. PATIENTS AND METHODS Through both in vitro and in vivo experiments, along with the analysis of alterations in the FBXW7-MCL1 axis and the YAP/TAZ-CCND1 pathway in patients with GISTs, before and after IM treatment. RESULTS MCL1 overexpression and activation of the YAP/TAZ-CCND1 pathway are induced in IM-resistant GIST cells and post-IM GIST samples. AT101, a BCL-2 inhibitor, exerts a pro-apoptotic effect on GIST cells by suppressing MCL1 overexpression, and the combination therapy of AT101 and IM exerts a stronger pro-apoptotic effect through modulation of IM activity regulated by the FBXW7-MCL1 axis. Furthermore, the suppression of AT101 on GIST growth and metastasis, by targeting the YAP/TAZ-CCND1 pathway, was confirmed through xenograft and metastasis mouse models. Notably, the antitumor activity of AT101 is maintained regardless of the IM sensitivity of GIST cells, whereas AT101 enhances and restores IM activities in both GIST-T1 and IM-resistant GIST cells. CONCLUSIONS AT101 exerts a strong antitumor activity by targeting both the FBXW7-MCL1 axis and the YAP/TAZ-CCND1 pathway, suggesting that AT101 monotherapy, and its combination with IM, are worth further investigating in clinical trials.
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Affiliation(s)
- Xiyu Wu
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kohei Yamashita
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Meiyue Lou
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Chihiro Matsumoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Weiliyun Zhang
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Masaaki Iwatsuki
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
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2
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Hu S, Ye J, Wang K, Xiong Y, Nie X. Inhibition of miR-9 Combined With Cisplatin Targeting APE1 Against Angiogenesis in Osteosarcoma. J Craniofac Surg 2024; 35:2189-2193. [PMID: 38771203 DOI: 10.1097/scs.0000000000010325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 04/13/2024] [Indexed: 05/22/2024] Open
Abstract
Osteosarcoma (OS) is a highly malignant tumor, and chemotherapy resistance suggests poor prognosis in OS patients. In this study, the authors discovered that miR-9 has a pro-angiogenic role in OS. The anti-angiogenic effects of cisplatin were greatly increased when miR-9 was suppressed in OS. In addition, the authors demonstrated that miR-9 plays a pro-angiogenic role by targeting apoptosis-inducing factor 1 (APE1) in OS. Importantly, our in vivo experiments showed that inhibition of miR-9 combined with cisplatin could suppress xenograft tumor growth by targeting APE1 and decreasing angiogenesis in OS. In summary, our results suggest that miR-9 plays a role as a tumor promoter, and inhibiting miR-9 and APE1 is a new strategy for inhibiting OS angiogenesis and chemotherapy resistance.
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Affiliation(s)
- Sunqiang Hu
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou
| | - Jiaqi Ye
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou
| | - Keyu Wang
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou
| | - Yan Xiong
- Department of Orthopaedics, Daping Hospital, Army Medical University, Chongqing, China
| | - Xin Nie
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou
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3
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Gohil D, Sarker AH, Roy R. Base Excision Repair: Mechanisms and Impact in Biology, Disease, and Medicine. Int J Mol Sci 2023; 24:14186. [PMID: 37762489 PMCID: PMC10531636 DOI: 10.3390/ijms241814186] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/12/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Base excision repair (BER) corrects forms of oxidative, deamination, alkylation, and abasic single-base damage that appear to have minimal effects on the helix. Since its discovery in 1974, the field has grown in several facets: mechanisms, biology and physiology, understanding deficiencies and human disease, and using BER genes as potential inhibitory targets to develop therapeutics. Within its segregation of short nucleotide (SN-) and long patch (LP-), there are currently six known global mechanisms, with emerging work in transcription- and replication-associated BER. Knockouts (KOs) of BER genes in mouse models showed that single glycosylase knockout had minimal phenotypic impact, but the effects were clearly seen in double knockouts. However, KOs of downstream enzymes showed critical impact on the health and survival of mice. BER gene deficiency contributes to cancer, inflammation, aging, and neurodegenerative disorders. Medicinal targets are being developed for single or combinatorial therapies, but only PARP and APE1 have yet to reach the clinical stage.
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Affiliation(s)
- Dhara Gohil
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA;
| | - Altaf H. Sarker
- Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA;
| | - Rabindra Roy
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA;
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4
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Chu YD, Chen CW, Lai MW, Lim SN, Lin WR. Bioenergetic alteration in gastrointestinal cancers: The good, the bad and the ugly. World J Gastroenterol 2023; 29:4499-4527. [PMID: 37621758 PMCID: PMC10445009 DOI: 10.3748/wjg.v29.i29.4499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/23/2023] [Accepted: 07/03/2023] [Indexed: 08/02/2023] Open
Abstract
Cancer cells exhibit metabolic reprogramming and bioenergetic alteration, utilizing glucose fermentation for energy production, known as the Warburg effect. However, there are a lack of comprehensive reviews summarizing the metabolic reprogramming, bioenergetic alteration, and their oncogenetic links in gastrointestinal (GI) cancers. Furthermore, the efficacy and treatment potential of emerging anticancer drugs targeting these alterations in GI cancers require further evaluation. This review highlights the interplay between aerobic glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS) in cancer cells, as well as hypotheses on the molecular mechanisms that trigger this alteration. The role of hypoxia-inducible transcription factors, tumor suppressors, and the oncogenetic link between hypoxia-related enzymes, bioenergetic changes, and GI cancer are also discussed. This review emphasizes the potential of targeting bioenergetic regulators for anti-cancer therapy, particularly for GI cancers. Emphasizing the potential of targeting bioenergetic regulators for GI cancer therapy, the review categorizes these regulators into aerobic glycolysis/ lactate biosynthesis/transportation and TCA cycle/coupled OXPHOS. We also detail various anti-cancer drugs and strategies that have produced pre-clinical and/or clinical evidence in treating GI cancers, as well as the challenges posed by these drugs. Here we highlight that understanding dysregulated cancer cell bioenergetics is critical for effective treatments, although the diverse metabolic patterns present challenges for targeted therapies. Further research is needed to comprehend the specific mechanisms of inhibiting bioenergetic enzymes, address side effects, and leverage high-throughput multi-omics and spatial omics to gain insights into cancer cell heterogeneity for targeted bioenergetic therapies.
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Affiliation(s)
- Yu-De Chu
- Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Chun-Wei Chen
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ming-Wei Lai
- Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Siew-Na Lim
- Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Wey-Ran Lin
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
- Department of Medicine, Chang Gung University, Taoyuan 333, Taiwan
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5
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Malfatti MC, Bellina A, Antoniali G, Tell G. Revisiting Two Decades of Research Focused on Targeting APE1 for Cancer Therapy: The Pros and Cons. Cells 2023; 12:1895. [PMID: 37508559 PMCID: PMC10378182 DOI: 10.3390/cells12141895] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/06/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
APE1 is an essential endodeoxyribonuclease of the base excision repair pathway that maintains genome stability. It was identified as a pivotal factor favoring tumor progression and chemoresistance through the control of gene expression by a redox-based mechanism. APE1 is overexpressed and serum-secreted in different cancers, representing a prognostic and predictive factor and a promising non-invasive biomarker. Strategies directly targeting APE1 functions led to the identification of inhibitors showing potential therapeutic value, some of which are currently in clinical trials. Interestingly, evidence indicates novel roles of APE1 in RNA metabolism that are still not fully understood, including its activity in processing damaged RNA in chemoresistant phenotypes, regulating onco-miRNA maturation, and oxidized RNA decay. Recent data point out a control role for APE1 in the expression and sorting of onco-miRNAs within secreted extracellular vesicles. This review is focused on giving a portrait of the pros and cons of the last two decades of research aiming at the identification of inhibitors of the redox or DNA-repair functions of APE1 for the definition of novel targeted therapies for cancer. We will discuss the new perspectives in cancer therapy emerging from the unexpected finding of the APE1 role in miRNA processing for personalized therapy.
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Affiliation(s)
- Matilde Clarissa Malfatti
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Alessia Bellina
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Giulia Antoniali
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Gianluca Tell
- Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, 33100 Udine, Italy
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6
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Inhibition of APE1 Expression Enhances the Antitumor Activity of Olaparib in Triple-Negative Breast Cancer. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:6048017. [PMID: 35463096 PMCID: PMC9020940 DOI: 10.1155/2022/6048017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 03/28/2022] [Accepted: 04/04/2022] [Indexed: 11/17/2022]
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that is prone to recurrence and metastasis. Because of the lack of expression of estrogen receptor (ER) and progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) in TNBC, treatment methods are greatly limited. In this study, the proliferation inhibition and apoptosis-inducing effects of PARP1 inhibitors in TNBC breast cancer cells and in vivo xenograft animal models were examined to investigate the molecular role of APE1 in PARP1-targeted therapy. In TNBC patients, the expression of APE1 and PARP1 were positively correlated, and high expression of APE1 and PARP1 was associated with poor survival of TNBC. Our results indicated that knockdown APE1 could increase the sensitivity of olaparib in the treatment of TNBC. In conclusion, the results of this study will not only clarify the molecular role of APE1 in PARP1-targeted therapy for TNBC but also provide a theoretical basis for the future clinical application of targeting APE1 and PARP1 in the treatment of refractory TNBC.
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7
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Mayer M, Berger A, Leischner C, Renner O, Burkard M, Böcker A, Noor S, Weiland T, Weiss TS, Busch C, Lauer UM, Bischoff SC, Venturelli S. Preclinical Efficacy and Toxicity Analysis of the Pan-Histone Deacetylase Inhibitor Gossypol for the Therapy of Colorectal Cancer or Hepatocellular Carcinoma. Pharmaceuticals (Basel) 2022; 15:ph15040438. [PMID: 35455435 PMCID: PMC9028974 DOI: 10.3390/ph15040438] [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: 02/03/2022] [Revised: 03/17/2022] [Accepted: 03/30/2022] [Indexed: 11/18/2022] Open
Abstract
Gossypol, a sesquiterpenoid found in cotton seeds, exerts anticancer effects on several tumor entities due to inhibition of DNA synthesis and other mechanisms. In clinical oncology, histone deacetylase inhibitors (HDACi) are applied as anticancer compounds. In this study, we examined whether gossypol harbors HDAC inhibiting activity. In vitro analyses showed that gossypol inhibited class I, II, and IV HDAC, displaying the capability to laterally interact with the respective catalytic center and is, therefore, classified as a pan-HDAC inhibitor. Next, we studied the effects of gossypol on human-derived hepatoma (HepG2) and colon carcinoma (HCT-116) cell lines and found that gossypol induced hyperacetylation of histone protein H3 and/or tubulin within 6 h. Furthermore, incubation with different concentrations of gossypol (5–50 µM) over a time period of 96 h led to a prominent reduction in cellular viability and proliferation of hepatoma (HepG2, Hep3B) and colon carcinoma (HCT-116, HT-29) cells. In-depth analysis of underlying mechanisms showed that gossypol induced apoptosis via caspase activation. For pre-clinical evaluation, toxicity analyses showed toxic effects of gossypol in vitro toward non-malignant primary hepatocytes (PHH), the colon-derived fibroblast cell line CCD-18Co, and the intestinal epithelial cell line CCD 841 CoN at concentrations of ≥5 µM, and embryotoxicity in chicken embryos at ≥2.5 µM. In conclusion, the pronounced inhibitory capacity of gossypol on cancer cells was characterized, and pan-HDACi activity was detected in silico, in vitro, by inhibiting individual HDAC isoenzymes, and on protein level by determining histone acetylation. However, for clinical application, further chemical optimization is required to decrease cellular toxicity.
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Affiliation(s)
- Mascha Mayer
- Institute of Nutritional Medicine and Prevention, University of Hohenheim, 70599 Stuttgart, Germany;
| | - Alexander Berger
- Department of Internal Medicine VIII, University Hospital Tuebingen, 72076 Tuebingen, Germany; (A.B.); (T.W.); (U.M.L.)
| | - Christian Leischner
- Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, 70599 Stuttgart, Germany; (C.L.); (O.R.); (M.B.)
| | - Olga Renner
- Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, 70599 Stuttgart, Germany; (C.L.); (O.R.); (M.B.)
| | - Markus Burkard
- Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, 70599 Stuttgart, Germany; (C.L.); (O.R.); (M.B.)
| | | | - Seema Noor
- Department of Dermatology, Eberhard Karls University of Tuebingen, 72076 Tuebingen, Germany;
| | - Timo Weiland
- Department of Internal Medicine VIII, University Hospital Tuebingen, 72076 Tuebingen, Germany; (A.B.); (T.W.); (U.M.L.)
| | - Thomas S. Weiss
- Center for Liver Cell Research, Children’s University Hospital (KUNO), University Hospital Regensburg, 93042 Regensburg, Germany;
| | | | - Ulrich M. Lauer
- Department of Internal Medicine VIII, University Hospital Tuebingen, 72076 Tuebingen, Germany; (A.B.); (T.W.); (U.M.L.)
- German Cancer Consortium (DKTK), DKFZ Partner Site, 72076 Tuebingen, Germany
| | - Stephan C. Bischoff
- Institute of Nutritional Medicine and Prevention, University of Hohenheim, 70599 Stuttgart, Germany;
- Correspondence: (S.C.B.); (S.V.); Tel.: +49-711-459-24100 (S.C.B.); +49-711-459-24195 (S.V.)
| | - Sascha Venturelli
- Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, 70599 Stuttgart, Germany; (C.L.); (O.R.); (M.B.)
- Department of Vegetative and Clinical Physiology, Institute of Physiology, University of Tuebingen, 72074 Tuebingen, Germany
- Correspondence: (S.C.B.); (S.V.); Tel.: +49-711-459-24100 (S.C.B.); +49-711-459-24195 (S.V.)
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8
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Demirbağ-Sarikaya S, Çakir H, Gözüaçik D, Akkoç Y. Crosstalk between autophagy and DNA repair systems. ACTA ACUST UNITED AC 2021; 45:235-252. [PMID: 34377049 PMCID: PMC8313936 DOI: 10.3906/biy-2103-51] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 06/09/2021] [Indexed: 12/15/2022]
Abstract
Autophagy and DNA repair are two essential biological mechanisms that maintain cellular homeostasis. Impairment of these mechanisms was associated with several pathologies such as premature aging, neurodegenerative diseases, and cancer. Intrinsic or extrinsic stress stimuli (e.g., reactive oxygen species or ionizing radiation) cause DNA damage. As a biological stress response, autophagy is activated following insults that threaten DNA integrity. Hence, in collaboration with DNA damage repair and response mechanisms, autophagy contributes to the maintenance of genomic stability and integrity. Yet, connections and interactions between these two systems are not fully understood. In this review article, current status of the associations and crosstalk between autophagy and DNA repair systems is documented and discussed.
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Affiliation(s)
| | - Hatice Çakir
- SUNUM Nanotechnology Research and Application Center, İstanbul Turkey
| | - Devrim Gözüaçik
- SUNUM Nanotechnology Research and Application Center, İstanbul Turkey.,Koç University School of Medicine, İstanbul Turkey.,Koç University Research Center for Translational Medicine (KUTTAM), İstanbul Turkey
| | - Yunus Akkoç
- Koç University Research Center for Translational Medicine (KUTTAM), İstanbul Turkey
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9
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Base excision repair and its implications to cancer therapy. Essays Biochem 2021; 64:831-843. [PMID: 32648895 PMCID: PMC7588666 DOI: 10.1042/ebc20200013] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/16/2020] [Accepted: 06/19/2020] [Indexed: 12/15/2022]
Abstract
Base excision repair (BER) has evolved to preserve the integrity of DNA following cellular oxidative stress and in response to exogenous insults. The pathway is a coordinated, sequential process involving 30 proteins or more in which single strand breaks are generated as intermediates during the repair process. While deficiencies in BER activity can lead to high mutation rates and tumorigenesis, cancer cells often rely on increased BER activity to tolerate oxidative stress. Targeting BER has been an attractive strategy to overwhelm cancer cells with DNA damage, improve the efficacy of radiotherapy and/or chemotherapy, or form part of a lethal combination with a cancer specific mutation/loss of function. We provide an update on the progress of inhibitors to enzymes involved in BER, and some of the challenges faced with targeting the BER pathway.
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10
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Yang F, Yan Z, Nie W, Liu Z, Cheng X, Wang W, Shao C, Fu G, Yu Y. LACTB and LC3 could serve as potential biomarkers of gastric cancer to neoadjuvant chemotherapy with oxaliplatin plus S-1. Oncol Lett 2021; 21:470. [PMID: 33907580 PMCID: PMC8063359 DOI: 10.3892/ol.2021.12731] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 03/17/2021] [Indexed: 01/31/2023] Open
Abstract
The present study investigated and evaluated the correlation between the expression of LACTB and LC3 and the clinical outcomes of patients with advanced gastric cancer treated with oxaliplatin plus S-1 neoadjuvant chemotherapy (NACT). A total of 51 patients with advanced gastric cancer underwent NACT treatment between June 2015 and June 2017. Pathomorphological changes in gastric cancer were analyzed by H&E staining. The expression level and subcellular localization of LACTB and LC3 in paraffin-embedded biopsies were detected by immunohistochemistry and immunofluorescence. The mRNA and protein expression of LACTB were investigated by reverse transcription quantitative polymerase chain reaction and Western blotting, respectively. Statistical analysis was performed to determine the association between the expression of LACTB and LC3 and clinical chemotherapy efficacy of NACT for gastric cancer. Among the 51 patients, 3 (5.88%), 27 (52.94%), 13 (25.49%) and 8 (15.69%) displayed complete remission, partial remission, stable disease and progressive disease, respectively. The rate of decreased LACTB expression was 68.6%, while the rate of increased LC3 expression was 60.8%. Furthermore, there was a significant negative correlation between the expression of LACTB and that of LC3 following NACT (P<0.001). High expression of LC3 (P<0.01) and low expression of LACTB (P<0.01) were associated with a poor response of patients with advanced gastric cancer to NACT. In conclusion, the expression of LACTB and LC3 may serve as a promising novel biomarker for determining the prognosis of patients with advanced gastric cancer receiving NACT, while its potential clinical significance requires further elucidation.
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Affiliation(s)
- Fang Yang
- Department of Pathology, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China.,School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China.,Laboratory Department of Guizhou Cancer Hospital, Guiyang, Guizhou 550004, P.R. China
| | - Zhiqiang Yan
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Wei Nie
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Zeying Liu
- Laboratory Department of Guizhou Cancer Hospital, Guiyang, Guizhou 550004, P.R. China
| | - Xingzhen Cheng
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Wei Wang
- Laboratory Department of Guizhou Cancer Hospital, Guiyang, Guizhou 550004, P.R. China
| | - Chunyan Shao
- Laboratory Department of Guizhou Cancer Hospital, Guiyang, Guizhou 550004, P.R. China
| | - Gui Fu
- Laboratory Department of Guizhou Cancer Hospital, Guiyang, Guizhou 550004, P.R. China
| | - Yanni Yu
- Department of Pathology, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
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11
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Kaleağasıoğlu F, Ali DM, Berger MR. Multiple Facets of Autophagy and the Emerging Role of Alkylphosphocholines as Autophagy Modulators. Front Pharmacol 2020; 11:547. [PMID: 32410999 PMCID: PMC7201076 DOI: 10.3389/fphar.2020.00547] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 04/09/2020] [Indexed: 12/13/2022] Open
Abstract
Autophagy is a highly conserved multistep process and functions as passage for degrading and recycling protein aggregates and defective organelles in eukaryotic cells. Based on the nature of these materials, their size and degradation rate, four types of autophagy have been described, i.e. chaperone mediated autophagy, microautophagy, macroautophagy, and selective autophagy. One of the major regulators of this process is mTOR, which inhibits the downstream pathway of autophagy following the activation of its complex 1 (mTORC1). Alkylphosphocholine (APC) derivatives represent a novel class of antineoplastic agents that inhibit the serine-threonine kinase Akt (i.e. protein kinase B), which mediates cell survival and cause cell cycle arrest. They induce autophagy through inhibition of the Akt/mTOR cascade. They interfere with phospholipid turnover and thus modify signaling chains, which start from the cell membrane and modulate PI3K/Akt/mTOR, Ras-Raf-MAPK/ERK and SAPK/JNK pathways. APCs include miltefosine, perifosine, and erufosine, which represent the first-, second- and third generation of this class, respectively. In a high fraction of human cancers, constitutively active oncoprotein Akt1 suppresses autophagy in vitro and in vivo. mTOR is a down-stream target for Akt, the activation of which suppresses autophagy. However, treatment with APC derivatives will lead to dephosphorylation (hence deactivation) of mTOR and thus induces autophagy. Autophagy is a double-edged sword and may result in chemotherapeutic resistance as well as cancer cell death when apoptotic pathways are inactive. APCs display differential autophagy induction capabilities in different cancer cell types. Therefore, autophagy-dependent cellular responses need to be well understood in order to improve the chemotherapeutic outcome.
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Affiliation(s)
- Ferda Kaleağasıoğlu
- Department of Pharmacology, Faculty of Medicine, Near East University, Mersin, Turkey
| | - Doaa M. Ali
- Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Pharmacology and Experimental Therapeutics, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Martin R. Berger
- Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
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12
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Manoel-Caetano FS, Rossi AFT, Calvet de Morais G, Severino FE, Silva AE. Upregulation of the APE1 and H2AX genes and miRNAs involved in DNA damage response and repair in gastric cancer. Genes Dis 2019; 6:176-184. [PMID: 31194025 PMCID: PMC6545450 DOI: 10.1016/j.gendis.2019.03.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Accepted: 03/28/2019] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer remains one of the leading causes of cancer-related death worldwide, and most of the cases are associated with Helicobacter pylori infection. This bacterium promotes the production of reactive oxygen species (ROS), which cause DNA damage in gastric epithelial cells. In this study, we evaluated the expression of important genes involved in the recognition of DNA damage (ATM, ATR, and H2AX) and ROS-induced damage repair (APE1) and the expression of some miRNAs (miR-15a, miR-21, miR-24, miR-421 and miR-605) that target genes involved in the DNA damage response (DDR) in 31 fresh tissues of gastric cancer. Cytoscape v3.1.1 was used to construct the postulated miRNA:mRNA interaction network. Analysis performed by real-time quantitative PCR exhibited significantly increased levels of the APE1 (RQ = 2.55, p < 0.0001) and H2AX (RQ = 2.88, p = 0.0002) genes beyond the miR-421 and miR-605 in the gastric cancer samples. In addition, significantly elevated levels of miR-21, miR-24 and miR-421 were observed in diffuse-type gastric cancer. Correlation analysis reinforced some of the gene:gene (ATM/ATR/H2AX) and miRNA:mRNA relationships obtained also with the interaction network. Thus, our findings show that tumor cells from gastric cancer presents deregulation of genes and miRNAs that participate in the recognition and repair of DNA damage, which could confer an advantage to cell survival and proliferation in the tumor microenvironment.
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Affiliation(s)
- Fernanda S Manoel-Caetano
- Department of Biology, UNESP, São Paulo State University, Campus of São José do Rio Preto, Rua Cristóvão Colombo, 2265, 15.054-000, São José do Rio Preto, São Paulo, Brazil
| | - Ana Flávia T Rossi
- Department of Biology, UNESP, São Paulo State University, Campus of São José do Rio Preto, Rua Cristóvão Colombo, 2265, 15.054-000, São José do Rio Preto, São Paulo, Brazil
| | - Gabriela Calvet de Morais
- Department of Biology, UNESP, São Paulo State University, Campus of São José do Rio Preto, Rua Cristóvão Colombo, 2265, 15.054-000, São José do Rio Preto, São Paulo, Brazil
| | - Fábio Eduardo Severino
- Department of Surgery and Orthopedics, Faculty of Medicine, UNESP, São Paulo State University, Campus of Botucatu, Av. Prof. Mário Rubens Guimarães Montenegro, s/n, 18.618-687, Botucatu, São Paulo, Brazil
| | - Ana Elizabete Silva
- Department of Biology, UNESP, São Paulo State University, Campus of São José do Rio Preto, Rua Cristóvão Colombo, 2265, 15.054-000, São José do Rio Preto, São Paulo, Brazil
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13
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Arsenic Trioxide and (-)-Gossypol Synergistically Target Glioma Stem-Like Cells via Inhibition of Hedgehog and Notch Signaling. Cancers (Basel) 2019; 11:cancers11030350. [PMID: 30871073 PMCID: PMC6468469 DOI: 10.3390/cancers11030350] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 02/28/2019] [Accepted: 03/07/2019] [Indexed: 01/08/2023] Open
Abstract
Glioblastoma is one of the deadliest malignancies and is virtually incurable. Accumulating evidence indicates that a small population of cells with a stem-like phenotype is the major culprit of tumor recurrence. Enhanced DNA repair capacity and expression of stemness marker genes are the main characteristics of these cells. Elimination of this population might delay or prevent tumor recurrence following radiochemotherapy. The aim of this study was to analyze whether interference with the Hedgehog signaling (Hh) pathway or combined Hh/Notch blockade using small-molecule inhibitors can efficiently target these cancer stem cells and sensitize them to therapy. Using tumor sphere lines and primary patient-derived glioma cultures we demonstrate that the Hh pathway inhibitor GANT61 (GANT) and the arsenic trioxide (ATO)-mediated Hh/Notch inhibition are capable to synergistically induce cell death in combination with the natural anticancer agent (−)-Gossypol (Gos). Only ATO in combination with Gos also strongly decreased stemness marker expression and prevented sphere formation and recovery. These synergistic effects were associated with distinct proteomic changes indicating diminished DNA repair and markedly reduced stemness. Finally, using an organotypic brain slice transplantation model, we show that combined ATO/Gos treatment elicits strong growth inhibition or even complete elimination of tumors. Collectively, our data show for the first time that ATO and Gos, two drugs that can be used in the clinic, represent a promising targeted therapy approach for the synergistic elimination of glioma stem-like cells.
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14
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Benvenuto M, Mattera R, Sticca JI, Rossi P, Cipriani C, Giganti MG, Volpi A, Modesti A, Masuelli L, Bei R. Effect of the BH3 Mimetic Polyphenol (-)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant Mesothelioma. Front Pharmacol 2018; 9:1269. [PMID: 30459622 PMCID: PMC6232343 DOI: 10.3389/fphar.2018.01269] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 10/17/2018] [Indexed: 01/02/2023] Open
Abstract
Malignant mesothelioma (MM) is a primary tumor arising from mesothelial cells. The survival of MM patients following traditional chemotherapy is poor, thus innovative treatments for MM are needed. (-)-gossypol (AT-101) is a BH3 mimetic compound which possesses anti-tumoral activity by targeting multiple signaling transduction pathways. Several clinical trials employing AT-101 have been performed and some of them are still ongoing. Accordingly, we investigated the in vitro effects of AT-101 on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis and autophagy of human (MM-B1, H-Meso-1, and MM-F1) and mouse (#40a) MM cell lines. In addition, we explored the in vivo anti-tumor activities of AT-101 in a mouse model, in which the transplantation of MM cells induces ascites in the peritoneal space. AT-101 inhibited in vitro MM cells survival in a dose- and time-dependent manner and triggered autophagy, but the process was then blocked and was coincident with apoptosis activation. To confirm the effect of AT-101 in inducing the apoptosis of MM cells, MM cells were simultaneously treated with AT-101 and with the caspase inhibitor, Z-VAD-FMK. Z-VAD-FMK was able to significantly reduce the number of cells in the subG1 phase compared to the treatment with AT-101 alone. This result corroborates the induction of cell death by apoptosis following treatment with AT-101. Indeed, Western blotting results showed that AT-101 increases Bax/Bcl-2 ratio, modulates p53 expression, activates caspase 9 and the cleavage of PARP-1. In addition, the treatment with AT-101 was able to: (a) decrease the ErbB2 protein expression; (b) increase the EGFR protein expression; (c) affect the phosphorylation of ERK1/2, p38 and AKT; (d) stimulate JNK1/2 and c-jun phosphorylation. Our in vivo results showed that the intraperitoneal administration of AT-101 increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of developing tumors. Our findings may have important implications for the design of MM therapies by employing AT-101 as an anticancer agent in combination with standard therapies.
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Affiliation(s)
- Monica Benvenuto
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Rosanna Mattera
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Joshua Ismaele Sticca
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Piero Rossi
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
| | - Chiara Cipriani
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
| | - Maria Gabriella Giganti
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Antonio Volpi
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Andrea Modesti
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Laura Masuelli
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Roberto Bei
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy
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15
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Feltes BC. Architects meets Repairers: The interplay between homeobox genes and DNA repair. DNA Repair (Amst) 2018; 73:34-48. [PMID: 30448208 DOI: 10.1016/j.dnarep.2018.10.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 10/30/2018] [Indexed: 02/07/2023]
Abstract
Homeobox genes are widely considered the major protagonists of embryonic development and tissue formation. For the past decades, it was established that the deregulation of these genes is intimately related to developmental abnormalities and a broad range of diseases in adults. Since the proper regulation and expression of homeobox genes are necessary for a successful developmental program and tissue function, their relation to DNA repair mechanisms become a necessary discussion. However, important as it is, studies focused on the interplay between homeobox genes and DNA repair are scarce, and there is no critical discussion on the subject. Hence, in this work, I aim to provide the first review of the current knowledge of the interplay between homeobox genes and DNA repair mechanisms, and offer future perspectives on this, yet, young ground for new researches. Critical discussion is conducted, together with a careful assessment of each reviewed topic.
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Affiliation(s)
- Bruno César Feltes
- Institute of Informatics, Department of Theoretical Informatics, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
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16
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APE1 stimulates EGFR-TKI resistance by activating Akt signaling through a redox-dependent mechanism in lung adenocarcinoma. Cell Death Dis 2018; 9:1111. [PMID: 30382076 PMCID: PMC6208429 DOI: 10.1038/s41419-018-1162-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 09/28/2018] [Accepted: 10/16/2018] [Indexed: 02/08/2023]
Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become the standard first-line treatment for advanced lung adenocarcinoma (LUAD) cancer patients with activating EGFR mutations. However, most patients show acquired resistance to EGFR-TKIs, thereby resulting in a modest overall survival benefit. Here, we found that expression level of APE1 was closely associated with TKI resistance in LUAD. Our clinical data show that level of APE1 was inversely correlated with progression-free survival rate and median time to progression in EGFR-mutated LUAD patients. Additionally, we observed increased expression of APE1 in TKI-resistant LUAD cell lines compared to their parental cell lines. Overexpression of APE1-protected TKI-sensitive LUAD cells from TKI-induced cell growth inhibition and cell death. In contrast, inhibition of APE1-enhanced TKI-induced apoptosis, cell growth inhibition and tumor growth inhibition in TKI-resistant LUAD. In addition, we identified that APE1 positively regulates Akt activation and APE1 overexpression-induced TKI resistance was attenuated by inhibition of Akt activity. Finally, we demonstrated that inhibition of the redox function of APE1 enhances the sensitivity of TKI-resistant LUAD cells to TKI treatment and inhibits Akt phosphorylation in TKI-resistant LUAD cells, but not by inhibition of the APE1 DNA repair function. Taken together, our data show that increased expression of APE1 significantly contributes to TKI resistance development in LUAD, and targeting APE1 may reverse acquired resistance of LUAD cells to TKI treatment. Additionally, our data show that APE1 regulates TKI resistance in LUAD cells by activating Akt signaling through a redox-dependent mechanism.
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17
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Abstract
Myeloid cell leukemia-1 (MCL-1), a member of antiapoptotic BCL-2 family proteins, is a key regulator of mitochondrial homeostasis. Frequent overexpression of MCL-1 in human primary and drug-resistant cancer cells makes it an attractive cancer therapeutic target. Significant progress has been made in the development of small-molecule MCL-1 inhibitors in recent years, and three MCL-1 selective inhibitors have advanced to clinical trials. This review briefly discusses recent advances in the development of small molecules targeting MCL-1 for cancer therapy.
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Affiliation(s)
- Weiguo Xiang
- Department of Internal Medicine, University of Michigan Medical School,
| | - Chao-Yie Yang
- Department of Internal Medicine, University of Michigan Medical School,
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA,
| | - Longchuan Bai
- Department of Internal Medicine, University of Michigan Medical School,
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA,
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18
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Qin F, Zhang H, Huang Y, Yang L, Yu F, Liu X, Fu L, Gu F, Ma Y. Effect of dihydropyrimidine dehydrogenase single nucleotide polymorphisms on prognosis of breast cancer patients with chemotherapy. Oncotarget 2017; 8:112060-112075. [PMID: 29340111 PMCID: PMC5762379 DOI: 10.18632/oncotarget.23033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 11/26/2017] [Indexed: 01/01/2023] Open
Abstract
Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate to guide patient selection for personalized cancer treatments. DPD (dihydropyrimidine dehydrogenase, encoded by DPYD gene) is the initial and rate-limiting enzyme of metabolic pathway of fluoropyrimidines, and fluoropyrimidines are common used drug therapies for breast cancer. Previous studies on DPYD polymorphism were mainly focused on its association with fluoropyrimidines toxicity. In our present study, 5 DPYD single nucleotide polymorphisms status was detected from tumor tissues of 331 invasive breast cancer patients using standard techniques. We for the first time investigated the prognostic significance of DPYD polymorphisms in breast cancer. We demonstrated non-luminal breast cancer patients carrying DPYD c.1627A>G AG/GG treated with fluoropyrimidine-based regimen presented a shorter overall survival and progression-free survival than carriers treated with non-fluoropyrimidine regimen. However, non-luminal DPYD c.1627A>G AG/GG carriers treated with TE (taxane and anthracycline)-based regimen showed a better prognosis compared with carriers treated with non-TE regimen. Our results suggested TE-based chemotherapy was a suitable regimen for non-luminal patients with DPYD c.1627A>G AG/GG genotype and fluoropyrimidine-based regimen should not be recommended for those patients. Our findings provided a novel strategy, which will guide clinicians to choose more precise chemotherapy treatment for breast cancer patients.
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Affiliation(s)
- Fengxia Qin
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Huikun Zhang
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Yong Huang
- Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Limin Yang
- Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Feng Yu
- Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Xiaoli Liu
- Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Li Fu
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Feng Gu
- Department of Breast Cancer Pathology and Research Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Yongjie Ma
- Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,National Clinical Research Center for Cancer, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
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19
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Yuan CL, He F, Ye JZ, Wu HN, Zhang JY, Liu ZH, Li YQ, Luo XL, Lin Y, Liang R. APE1 overexpression is associated with poor survival in patients with solid tumors: a meta-analysis. Oncotarget 2017; 8:59720-59728. [PMID: 28938675 PMCID: PMC5601771 DOI: 10.18632/oncotarget.19814] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 07/18/2017] [Indexed: 01/13/2023] Open
Abstract
APE1 is known as a key mediator of DNA damage repair pathways, and its clinical significance in different types of cancer is well studied. Herein, we performed a meta-analysis to determine the association of APE1 expression and survival in different types of solid cancer. We searched all eligible publications in PubMed, Web of Science and Embase platforms from inception to January 2017 and found 15 relevant manuscripts. Overall survival (OS), 12- and 36-month survival rates, and hazard ratios (HRs) were extracted and analyzed. Heterogeneity and publication bias were also assessed. A subgroup analysis of the different subcellular locations of APE1 was also conducted. Patients with higher APE1 levels demonstrated lower 12- and 36-month survival rates than those with low APE1 levels (HR 2.00, 95% CI 1.33–3.00, P = 0.0009; HR 1.84, 95% CI 1.19–2.84, P = 0.006). Importantly, the pooled analysis showed that high levels of APE1 predict shorter OS (HR 1.44, 95% CI 1.13–1.83, P = 0.003). Subgroup analysis revealed that both nuclear and cytoplasmic expression levels of APE1 are important indicators of poor prognosis in solid tumors.
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Affiliation(s)
- Chun-Ling Yuan
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, P. R. China
| | - Fan He
- College of Arts and Sciences, University of South Florida, Tampa, FL, 33620, USA
| | - Jia-Zhou Ye
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, P. R. China
| | - Hui-Ni Wu
- School of Public Health, Sun Yat-sen University, Guangzhou, 510080, Guangdong, P. R. China
| | - Jin-Yan Zhang
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, P. R. China
| | - Zhi-Hui Liu
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, P. R. China
| | - Yong-Qiang Li
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, P. R. China
| | - Xiao-Ling Luo
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, P. R. China
| | - Yan Lin
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, P. R. China
| | - Rong Liang
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, P. R. China
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20
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Liang W, Wei X, Li Q, Dai N, Li CY, Deng Y, Jiang X, Tan XR, Dai XY, Li MX, Xu CX, Wang D, Zhong ZY. MicroRNA-765 Enhances the Anti-Angiogenic Effect of CDDP via APE1 in Osteosarcoma. J Cancer 2017; 8:1542-1551. [PMID: 28775773 PMCID: PMC5535709 DOI: 10.7150/jca.18680] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 02/26/2017] [Indexed: 12/22/2022] Open
Abstract
Human osteosarcoma (HOS) is the most common malignancy in children and adolescents and has a heterogeneous presentation and high mortality. Previous studies have shown that microRNAs contribute to RNA silencing and post-transcriptional regulation of gene expression. Here, we showed that significantly increased expression of miR-765 with or without CDDP (Cisplatin) down-regulates APE1 expression and angiogenesis-related markers (VEGF, FGF2, TGFβ, and CD34). Further investigation showed that miR-765 modulates osteosarcoma cell migration and angiogenesis following treatment with cisplatin in vitro and in vivo. MiR-765 increases the anti-angiogenic effect of CDDP in human osteosarcoma. Elucidation of the mechanism of the miR-765-APE1 axis in tumor progression of HOS will be beneficial in identifying biomarkers and therapeutic target of osteosarcoma.
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Affiliation(s)
- Wei Liang
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing,400042, China
| | - Xi Wei
- Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Qing Li
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing,400042, China
| | - Nan Dai
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing,400042, China
| | - Chong-Yi Li
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing,400042, China
| | - Yi Deng
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing,400042, China
| | - Xuan Jiang
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing,400042, China
| | - Xiao-Rong Tan
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing,400042, China
| | - Xiao-Yan Dai
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing,400042, China
| | - Meng-Xia Li
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing,400042, China
| | - Cheng-Xiong Xu
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing,400042, China
| | - Dong Wang
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing,400042, China
| | - Zhao-Yang Zhong
- Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing,400042, China
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21
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Wei X, Li YB, Li Y, Lin BC, Shen XM, Cui RL, Gu YJ, Gao M, Li YG, Zhang S. Prediction of Lymph Node Metastases in Gastric Cancer by Serum APE1 Expression. J Cancer 2017. [PMID: 28638465 PMCID: PMC5479256 DOI: 10.7150/jca.18615] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Aims: To investigate the functional role of serum Human apurinic/apyrimidinic endonuclease 1 (APE1) in prediction of lymph node metastasis in gastric cancer patients. Materials and methods: Serum samples were pre-operational collected from 86 patients with gastric cancer from Tianjin Medical University Cancer Institute and Hospital from March 2016 to August 2016. The serum of APE1 was measured by ELISA development kit and other CA242, CA724, CA199 and CEA levels by electrochemiluminescence assay. Results: The total of 86 patients with gastric cancer was classified into two groups (lymph node positive and negative groups). Using ELISA assay, we found out that the concentration of serum APE1 was higher in lymph node positive group than that of lymph node negative group. The receiver operating characteristic (ROC) curve was performed to analyze, indicating that area under the ROC curve of serum APE1 were better than those of each regular markers (CEA+CA199+CA242+CA724) or combination of these markers. Additionally, the APE1 overexpression was uncovered in tissue of gastric cancer patients with lymph nodes metastases, which is correlation with results of serum APE1. Conclusion: Serum APE1 was identified as a valuable marker for prediction of lymph node metastases in patients with gastric cancer.
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Affiliation(s)
- Xi Wei
- Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yi-Bo Li
- Department of general surgery, The first affiliated hospital of DaLian medical university
| | - Ying Li
- The Third Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Ben-Cheng Lin
- Tianjin Institute of Health and Environmental Medicine, Key Laboratory of Risk Assessment and Control Technology for Environment & Food Safety, Tianjin 300050, China
| | - Xiao-Min Shen
- Department of Clinical Laboratory, Tianjin second people' hospital
| | - Ran-Liang Cui
- Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Ya-Jun Gu
- School of Medical Laboratory, Tianjin Medical University
| | - Ming Gao
- Department of Thyroid and Cervical Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Yue-Guo Li
- Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Sheng Zhang
- Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
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22
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Laev SS, Salakhutdinov NF, Lavrik OI. Inhibitors of nuclease and redox activity of apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1). Bioorg Med Chem 2017; 25:2531-2544. [PMID: 28161249 DOI: 10.1016/j.bmc.2017.01.028] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 01/16/2017] [Accepted: 01/18/2017] [Indexed: 01/15/2023]
Abstract
Human apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional protein which is essential in the base excision repair (BER) pathway of DNA lesions caused by oxidation and alkylation. This protein hydrolyzes DNA adjacent to the 5'-end of an apurinic/apyrimidinic (AP) site to produce a nick with a 3'-hydroxyl group and a 5'-deoxyribose phosphate moiety or activates the DNA-binding activity of certain transcription factors through its redox function. Studies have indicated a role for APE1/Ref-1 in the pathogenesis of cancer and in resistance to DNA-interactive drugs. Thus, this protein has potential as a target in cancer treatment. As a result, major efforts have been directed to identify small molecule inhibitors against APE1/Ref-1 activities. These agents have the potential to become anticancer drugs. The aim of this review is to present recent progress in studies of all published small molecule APE1/Ref-1 inhibitors. The structures and activities of APE1/Ref-1 inhibitors, that target both DNA repair and redox activities, are presented and discussed. To date, there is an urgent need for further development of the design and synthesis of APE1/Ref-1 inhibitors due to high importance of this protein target.
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Affiliation(s)
- Sergey S Laev
- Vorozhtsov Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences, pr. akademika Lavrent'eva 9, Novosibirsk 630090, Russian Federation.
| | - Nariman F Salakhutdinov
- Vorozhtsov Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences, pr. akademika Lavrent'eva 9, Novosibirsk 630090, Russian Federation; Novosibirsk State University, Pirogova Str. 2, Novosibirsk 630090, Russian Federation
| | - Olga I Lavrik
- Novosibirsk State University, Pirogova Str. 2, Novosibirsk 630090, Russian Federation; Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Division, Russian Academy of Sciences, pr. akademika Lavrent'eva 8, Novosibirsk 630090, Russian Federation
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Yao M, Shang YY, Zhou ZW, Yang YX, Wu YS, Guan LF, Wang XY, Zhou SF, Wei X. The research on lapatinib in autophagy, cell cycle arrest and epithelial to mesenchymal transition via Wnt/ErK/PI3K-AKT signaling pathway in human cutaneous squamous cell carcinoma. J Cancer 2017; 8:220-226. [PMID: 28243326 PMCID: PMC5327371 DOI: 10.7150/jca.16850] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 11/10/2016] [Indexed: 01/09/2023] Open
Abstract
Cutaneous squamous cell carcinoma (cSCC) contributes to one of most common types of skin cancer. Epidermal growth factor receptor (EGFR) activation has been investigated to be associated with the development of cSCC. Lapatinib is an inhibitor targeting HER2/neu and EGFR pathway. We found that lapatinib can inhibit proliferation by enhancing apoptosis of human cSCC cell lines. The cSCC cell cycle distribution could be arrested in G2/M phase after lapatinib treatment. In the in vitro experiment, we found that lapatinib interrupted PI3K/AKT/mTOR signaling pathway in human cSCC cells. Furthermore, lapatinib could suppress epithelial to mesenchymal transition (EMT) via Wnt/ErK/PI3K-AKT signaling pathway to represent a promising anticancer drug for cSCC treatment.
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Affiliation(s)
- Ming Yao
- Department of Burns and Plastic Surgery, General Hospital, Ningxia Medical University, Yinchuan, People's Republic of China.; Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
| | - Yuan-Yuan Shang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.; Department of Dermatology, General Hospital, Ningxia Medical University
| | - Zhi-Wei Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
| | - Yin-Xue Yang
- Department of Colorectal Surgery, General Hospital, Ningxia Medical University
| | - Yin-Sheng Wu
- Department of Burns and Plastic Surgery, General Hospital, Ningxia Medical University, Yinchuan, People's Republic of China
| | - Li-Feng Guan
- Department of Burns and Plastic Surgery, General Hospital, Ningxia Medical University, Yinchuan, People's Republic of China
| | - Xin-Yu Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.; Department of Pharmacy, General Hospital, Ningxia Medical University, Yinchuan
| | - Shu-Feng Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
| | - Xi Wei
- Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
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