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Jiang Z, Xu Y, Yang L, Huang X, Bao J. Bile acid conjugated chitosan nanoparticles promote the proliferation and epithelial-mesenchymal transition of hepatocellular carcinoma by regulating the PI3K/Akt/mTOR pathway. Carbohydr Res 2024; 545:109296. [PMID: 39471534 DOI: 10.1016/j.carres.2024.109296] [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: 06/26/2024] [Revised: 10/19/2024] [Accepted: 10/22/2024] [Indexed: 11/01/2024]
Abstract
Bile acids have been known to play significant roles at certain physiological levels in gastrointestinal metabolism. Yet, they are known to be carcinogenic and aid in tumor progression in most cases, although the roles remain uncertain. Hence, we tested the cytotoxic potential of cholic acid (CA) loaded chitosan nanoparticles (CNPs) on Hep3B cells. The physicochemical properties of the CNPs synthesized with CA load (CA-CNPs) were determined using standard techniques such as ultraviolet-visible spectrophotometry (UV-Vis), fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), dynamic light scattering (DLS) and transmission electron microscopy (TEM). The characteristic peak for chitosan nanoparticles were observed for plain CNPs (pCNPs) and CA-CNPs at around 300 nm as per UV-Vis analysis. FTIR analysis indicated the possible trapping of CA onto CNPs as certain peaks were retained and some peaks were shifted. XRD analysis determined that the peaks representing CA and pCNPs were collectively obtained in CA-CNPs. As per DLS analysis, the particle size, PDI and ζ-potential of the CA-CNPs were 259 nm, 0.284 and 30.4 mV. Further, the CA-CNPs were non-cytotoxic on Hep3B cells at the maximum tested concentration of 500 μg/mL. The viability at 500 μg/mL of CA-CNPs was two-fold higher than 500 μg/mL of pCNPs. Also, the pCNPs were not hemolytic and therefore could not have played a role in the increase of viability after treatment with CA-CNPs, which indicates that CA posed a major role in increased viability of Hep3B cells. As per quantitative PCR (qPCR), the upregulated gene expressions of PI3K, Akt, mTORC2, cMyc, Fibronectin, hVPS34, Slug and ZEB1 and the downregulated expression of the tumor suppressor PTEN indicates that PI3K/Akt/mTOR pathway mediated the induction of epithelial-to-mesenchymal transition (EMT) in response to CA-CNPs treatment on Hep3B cells.
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Affiliation(s)
- Ziyu Jiang
- Department of Chemotherapy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China; Department of Oncology, Lianyungang Hospital Affiliated to Xuzhou Medical University, Lianyungang, 222002, China
| | - Yi Xu
- Phase I Clinical Trial Center, Lianyungang Hospital Affiliated to Xuzhou Medical University, Lianyungang, 222002, China
| | - Liu Yang
- Department of Colorectal Center, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
| | - Xing Huang
- Department of Pathology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Affifiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
| | - Jun Bao
- Department of Chemotherapy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China.
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Gupta I, Gaykalova DA. Unveiling the role of PIK3R1 in cancer: A comprehensive review of regulatory signaling and therapeutic implications. Semin Cancer Biol 2024; 106-107:58-86. [PMID: 39197810 DOI: 10.1016/j.semcancer.2024.08.004] [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: 05/07/2024] [Revised: 07/11/2024] [Accepted: 08/20/2024] [Indexed: 09/01/2024]
Abstract
Phosphoinositide 3-kinase (PI3K) is responsible for phosphorylating phosphoinositides to generate secondary signaling molecules crucial for regulating various cellular processes, including cell growth, survival, and metabolism. The PI3K is a heterodimeric enzyme complex comprising of a catalytic subunit (p110α, p110β, or p110δ) and a regulatory subunit (p85). The binding of the regulatory subunit, p85, with the catalytic subunit, p110, forms an integral component of the PI3K enzyme. PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) belongs to class IA of the PI3K family. PIK3R1 exhibits structural complexity due to alternative splicing, giving rise to distinct isoforms, prominently p85α and p55α. While the primary p85α isoform comprises multiple domains, including Src homology 3 (SH3) domains, a Breakpoint Cluster Region Homology (BH) domain, and Src homology 2 (SH2) domains (iSH2 and nSH2), the shorter isoform, p55α, lacks certain domains present in p85α. In this review, we will highlight the intricate regulatory mechanisms governing PI3K signaling along with the impact of PIK3R1 alterations on cellular processes. We will further delve into the clinical significance of PIK3R1 mutations in various cancer types and their implications for prognosis and treatment outcomes. Additionally, we will discuss the evolving landscape of targeted therapies aimed at modulating PI3K-associated pathways. Overall, this review will provide insights into the dynamic interplay of PIK3R1 in cancer, fostering advancements in precision medicine and the development of targeted interventions.
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Affiliation(s)
- Ishita Gupta
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Otorhinolaryngology-Head and Neck Surgery, Marlene & Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, MD, USA
| | - Daria A Gaykalova
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Otorhinolaryngology-Head and Neck Surgery, Marlene & Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
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3
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Su L, Zhao C, Sun B, Dou L, Wang C, Yang Z, Li T, Jin Y. Effects of exercise on muscle fiber conversion, muscle development and meat quality of Sunit sheep. Meat Sci 2024; 211:109440. [PMID: 38324956 DOI: 10.1016/j.meatsci.2024.109440] [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: 09/04/2023] [Revised: 01/22/2024] [Accepted: 01/26/2024] [Indexed: 02/09/2024]
Abstract
This study aimed to investigate the effects of exercise on muscle fiber conversion, muscle development and meat quality in the biceps femoris (BF) muscle of Sunit sheep. Twelve Sunit sheep with similar body weight were divided into two groups: control group (C group) and exercise group (E group), E group lambs underwent 6 km of exercise training per day for 90 d. The findings revealed that compared with the C group, exercise training enhanced the expression of MyHC IIa mRNA, decreased the number ratio of type IIB muscle fibers and the expression of MyHC IIb mRNA (P < 0.05). Furthermore, the E group lamb displayed higher creatine kinase (CK) activity, and lactic acid levels (P < 0.05), while glycogen content and lactic dehydrogenase (LDH) activity showed opposite trends (P < 0.05). Exercise significantly up-regulated the mRNA expression of AMP-activated protein kinase α1 (AMPKα1), sirtuin1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), cytochrome c oxidase IV (COX IV), protein kinase B (Akt), mammalian target of rapamycin (mTOR) and p70 Ribosomal S6 Kinase 1 (p70s6k1) (P < 0.05), suggesting exercise promoted muscle fiber conversion by mediating AMPK/PGC-1α pathway, and improved skeletal muscle development via Akt/mTOR pathway. Besides, backfat thickness and pH45min value in the E group decreased significantly, while the pH24, a*, and shear force value increased significantly (P < 0.05). To conclude, this study suggested that exercise training can be used to alter muscle fiber characteristics and muscle development in lamb production.
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Affiliation(s)
- Lin Su
- Department of Food Science, College of Food Science and Engineering, Inner Mongolia Agricultural University, Hohhot 010018, China; Integrative Research Base of Beef and Lamb Processing Technology, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Congying Zhao
- Department of Food Science, College of Food Science and Engineering, Inner Mongolia Agricultural University, Hohhot 010018, China; Integrative Research Base of Beef and Lamb Processing Technology, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Bing Sun
- Saihan District Center for Disease Control and Prevention, Hohhot 010010, China
| | - Lu Dou
- Department of Food Science, College of Food Science and Engineering, Inner Mongolia Agricultural University, Hohhot 010018, China; Integrative Research Base of Beef and Lamb Processing Technology, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Chenlei Wang
- Department of Food Science, College of Food Science and Engineering, Inner Mongolia Agricultural University, Hohhot 010018, China; Integrative Research Base of Beef and Lamb Processing Technology, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Zhihao Yang
- Department of Food Science, College of Food Science and Engineering, Inner Mongolia Agricultural University, Hohhot 010018, China; Integrative Research Base of Beef and Lamb Processing Technology, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Tianle Li
- Department of Food Science, College of Food Science and Engineering, Inner Mongolia Agricultural University, Hohhot 010018, China; Integrative Research Base of Beef and Lamb Processing Technology, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Ye Jin
- Department of Food Science, College of Food Science and Engineering, Inner Mongolia Agricultural University, Hohhot 010018, China; Integrative Research Base of Beef and Lamb Processing Technology, Inner Mongolia Agricultural University, Hohhot, 010018, China.
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Hu L, Shi J, Zhu Z, Lu X, Jiang H, Yu H, Liu H, Chen W. CRISPLD1 promotes gastric cancer progression by regulating the Ca 2+/PI3K-AKT signaling pathway. Heliyon 2024; 10:e27569. [PMID: 38486747 PMCID: PMC10938123 DOI: 10.1016/j.heliyon.2024.e27569] [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: 12/20/2023] [Revised: 03/01/2024] [Accepted: 03/01/2024] [Indexed: 03/17/2024] Open
Abstract
Gastric cancer (GC) is a malignant tumor with poor prognosis. Studies have shown that cysteine-rich secretory protein LCCL domain containing 1 (CRISPLD1) is associated with tumor progression. However, its role in GC is unclear. The present study aimed to determine the pathogenic mechanism of CRISPLD1 in GC. Analysis of public databases revealed high mRNA expression of CRISPLD1 in GC, which was associated with poor prognosis. Additionally, CRISPLD1 expression levels showed significant correlations with T stage, overall survival events, and stage. Knockdown of CRISPLD1 reduced cell proliferation, invasion, and migration. Furthermore, CRISPLD1 knockdown decreased intracellular calcium levels in GC cells and inhibited the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. Treatment with an AKT activator reversed the inhibitory effect of CRISPLD1 knockdown on GC cell migration and invasion. Our findings suggest that CRISPLD1 promotes tumor cell progression in GC by mediating intracellular calcium levels and activating the PI3K-AKT pathway, highlighting CRISPLD1 as a potential therapeutic target for GC.
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Affiliation(s)
- Liqiang Hu
- Graduate school of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | - Jianghua Shi
- Graduate school of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Zichen Zhu
- Graduate school of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Xuemei Lu
- Graduate school of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | - Huibo Jiang
- Graduate school of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | - Hanyang Yu
- School of Computer Science, University of Nottingham Ningbo China, Ningbo, China
| | - Hao Liu
- Graduate school of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | - Wei Chen
- Graduate school of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine of Zhejiang Province, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
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Zhu X, Zhang Y, Bian R, Zhu J, Shi W, Ye Y. ANLN Promotes the Proliferation and Migration of Gallbladder Cancer Cells via STRA6-Mediated Activation of PI3K/AKT Signaling. Cancers (Basel) 2024; 16:752. [PMID: 38398143 PMCID: PMC10887181 DOI: 10.3390/cancers16040752] [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: 01/15/2024] [Revised: 02/05/2024] [Accepted: 02/08/2024] [Indexed: 02/25/2024] Open
Abstract
The ANLN gene encodes anillin, a protein that binds to actin. Recent research has identified ANLN's function in the initiation and advancement of different cancers. However, its impact on gallbladder cancer (GBC) remains unexplored. This study aimed to elucidate its possible molecular mechanisms in GBC. ANLN expression was assessed using quantitative real-time polymerase chain reaction (QRT-PCR), Western blotting (WB), and immunohistochemistry (IHC), revealing elevated levels in GBC tissues. ANLN knockdown resulted in the inhibition of cell proliferation and migration, leading to apoptosis and cell cycle arrest. Conversely, ANLN overexpression had the opposite effects on GBC cells. In vivo experiments confirmed that ANLN knockdown inhibited GBC cell growth. RNA-seq and bioinformatics analysis revealed ANLN's function in activating the PI3K/AKT signaling pathway. We further confirmed that ANLN could upregulate STRA6 expression, which activated PI3K/AKT signaling to enhance the growth and movement of GBC cells. These findings demonstrate ANLN's involvement in GBC initiation and progression, suggesting its potential as a novel target for GBC.
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Affiliation(s)
- Xiang Zhu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China; (X.Z.); (Y.Z.)
- Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Yong Zhang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China; (X.Z.); (Y.Z.)
| | - Rui Bian
- Clinical Research and Innovation Center, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China
| | - Jiyue Zhu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China; (X.Z.); (Y.Z.)
| | - Weibin Shi
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China; (X.Z.); (Y.Z.)
| | - Yuanyuan Ye
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China; (X.Z.); (Y.Z.)
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Cao R, Guo S, Min L, Li P. Roles of Rictor alterations in gastrointestinal tumors (Review). Oncol Rep 2024; 51:37. [PMID: 38186315 PMCID: PMC10807360 DOI: 10.3892/or.2024.8696] [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: 04/05/2023] [Accepted: 11/28/2023] [Indexed: 01/09/2024] Open
Abstract
Gastrointestinal tumors account for five of the top 10 causes of mortality from all cancers (colorectal, liver, stomach, esophageal and pancreatic cancer). Mammalian target of rapamycin (mTOR) signaling is commonly dysregulated in various human cancers. As a core component of the mTOR complex 2 (mTORC2), Rictor is a key effector molecule of the PI3K/Akt pathway. A high alteration rate of Rictor has been observed in gastrointestinal tumors, and such Rictor alterations are often associated with resistance to chemotherapy and related adverse clinical outcomes. However, the exact roles of Rictor in gastrointestinal tumors remain elusive. The aim of the present study was to critically discuss the following: i) Mutation and biological characteristics of Rictor in tumors with a detailed overview of Rictor in cell proliferation, angiogenesis, apoptosis, autophagy and drug resistance; ii) the role of Rictor in tumors of the digestive system, particularly colorectal, hepatobiliary, gastric, esophageal and pancreatic cancer and cholangiocarcinoma; and iii) the current status and prospects of targeted therapy for Rictor by inhibiting Akt activation. Despite the growing realization of the importance of Rictor/mTORC2 in cancer, the underlying mechanistic details remain poorly understood; this needs to change in order for the development of efficient targeted therapies and re‑sensitization of therapy‑resistant cancers to be made possible.
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Affiliation(s)
- Ruizhen Cao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
| | - Shuilong Guo
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
| | - Li Min
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, P.R. China
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Li S, Chen JS, Li X, Bai X, Shi D. MNK, mTOR or eIF4E-selecting the best anti-tumor target for blocking translation initiation. Eur J Med Chem 2023; 260:115781. [PMID: 37669595 DOI: 10.1016/j.ejmech.2023.115781] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/29/2023] [Accepted: 08/29/2023] [Indexed: 09/07/2023]
Abstract
Overexpression of eIF4E is common in patients with various solid tumors and hematologic cancers. As a potential anti-cancer target, eIF4E has attracted extensive attention from researchers. At the same time, mTOR kinases inhibitors and MNK kinases inhibitors, which are directly related to regulation of eIF4E, have been rapidly developed. To explore the optimal anti-cancer targets among MNK, mTOR, and eIF4E, this review provides a detailed classification and description of the anti-cancer activities of promising compounds. In addition, the structures and activities of some dual-target inhibitors are briefly described. By analyzing the different characteristics of the inhibitors, it can be concluded that MNK1/2 and eIF4E/eIF4G interaction inhibitors are superior to mTOR inhibitors. Simultaneous inhibition of MNK and eIF4E/eIF4G interaction may be the most promising anti-cancer method for targeting translation initiation.
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Affiliation(s)
- Shuo Li
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, Shandong, PR China.
| | - Jia-Shu Chen
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, Shandong, PR China.
| | - Xiangqian Li
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, Shandong, PR China.
| | - Xiaoyi Bai
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, Shandong, PR China.
| | - Dayong Shi
- State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, Shandong, PR China.
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Chen X, Shi C, He M, Xiong S, Xia X. Endoplasmic reticulum stress: molecular mechanism and therapeutic targets. Signal Transduct Target Ther 2023; 8:352. [PMID: 37709773 PMCID: PMC10502142 DOI: 10.1038/s41392-023-01570-w] [Citation(s) in RCA: 295] [Impact Index Per Article: 147.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 06/17/2023] [Accepted: 07/14/2023] [Indexed: 09/16/2023] Open
Abstract
The endoplasmic reticulum (ER) functions as a quality-control organelle for protein homeostasis, or "proteostasis". The protein quality control systems involve ER-associated degradation, protein chaperons, and autophagy. ER stress is activated when proteostasis is broken with an accumulation of misfolded and unfolded proteins in the ER. ER stress activates an adaptive unfolded protein response to restore proteostasis by initiating protein kinase R-like ER kinase, activating transcription factor 6, and inositol requiring enzyme 1. ER stress is multifaceted, and acts on aspects at the epigenetic level, including transcription and protein processing. Accumulated data indicates its key role in protein homeostasis and other diverse functions involved in various ocular diseases, such as glaucoma, diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, achromatopsia, cataracts, ocular tumors, ocular surface diseases, and myopia. This review summarizes the molecular mechanisms underlying the aforementioned ocular diseases from an ER stress perspective. Drugs (chemicals, neurotrophic factors, and nanoparticles), gene therapy, and stem cell therapy are used to treat ocular diseases by alleviating ER stress. We delineate the advancement of therapy targeting ER stress to provide new treatment strategies for ocular diseases.
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Affiliation(s)
- Xingyi Chen
- Eye Center of Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
- Hunan Key Laboratory of Ophthalmology, Central South University, 410008, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Chaoran Shi
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Meihui He
- Eye Center of Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
- Hunan Key Laboratory of Ophthalmology, Central South University, 410008, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Siqi Xiong
- Eye Center of Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China.
- Hunan Key Laboratory of Ophthalmology, Central South University, 410008, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
| | - Xiaobo Xia
- Eye Center of Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China.
- Hunan Key Laboratory of Ophthalmology, Central South University, 410008, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
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Tang XH, Wu XL, Gan XJ, Wang YD, Jia FZ, Wang YX, Zhang Y, Gao XY, Li ZY. Using Normalized Carcinoembryonic Antigen and Carbohydrate Antigen 19 to Predict and Monitor the Efficacy of Neoadjuvant Chemotherapy in Locally Advanced Gastric Cancer. Int J Mol Sci 2023; 24:12192. [PMID: 37569566 PMCID: PMC10418931 DOI: 10.3390/ijms241512192] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 07/23/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are established prognostic biomarkers for patients with gastric cancer. However, their potential as predictive markers for neoadjuvant chemotherapy (NACT) efficacy has not been fully elucidated. METHODS We conducted a retrospective analysis to determine values of CEA and CA19-9 prior to NACT (pre-NACT) and after NACT (post-NACT) in 399 patients with locally advanced gastric cancer (LAGC) who received intended NACT and surgery. RESULTS Among the 399 patients who underwent NACT plus surgery, 132 patients (33.1%) had elevated pre-NACT CEA/CA19-9 values. Furthermore, either pre-NACT or post-NACT CEA /CA19-9 levels were significantly associated with prognosis (p = 0.0023) compared to patients with non-elevated levels. Moreover, among the patients, a significant proportion (73/132, 55.3%) achieved normalized CEA/CA19-9 following NACT, which is a strong marker of a favorable treatment response and survival benefits. In addition, the patients with normalized CEA/CA19-9 also had a prolonged survival compared to those who underwent surgery first (p = 0.0140), which may be attributed to the clearance of micro-metastatic foci. Additionally, the magnitude of CEA/CA19-9 changes did not exhibit a statistically significant prognostic value. CONCLUSIONS Normalization of CEA/CA19-9 is a strong biomarker for the effectiveness of treatment, and can thus be exploited to prolong the long-term survival of patients with LAGC.
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Affiliation(s)
- Xiao-Huan Tang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gas-Trointestinal Cancer Center, Ward I, Peking University Cancer Hospital & Institute, Beijing 100142, China; (X.-H.T.); (X.-L.W.)
| | - Xiao-Long Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gas-Trointestinal Cancer Center, Ward I, Peking University Cancer Hospital & Institute, Beijing 100142, China; (X.-H.T.); (X.-L.W.)
| | - Xue-Jun Gan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gas-Trointestinal Cancer Center, Ward I, Peking University Cancer Hospital & Institute, Beijing 100142, China; (X.-H.T.); (X.-L.W.)
| | - Yi-Ding Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gas-Trointestinal Cancer Center, Ward I, Peking University Cancer Hospital & Institute, Beijing 100142, China; (X.-H.T.); (X.-L.W.)
| | - Fang-Zhou Jia
- Biological Sample Bank, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yi-Xue Wang
- Biological Sample Bank, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yan Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gas-Trointestinal Cancer Center, Ward I, Peking University Cancer Hospital & Institute, Beijing 100142, China; (X.-H.T.); (X.-L.W.)
| | - Xiang-Yu Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gas-Trointestinal Cancer Center, Ward I, Peking University Cancer Hospital & Institute, Beijing 100142, China; (X.-H.T.); (X.-L.W.)
| | - Zi-Yu Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gas-Trointestinal Cancer Center, Ward I, Peking University Cancer Hospital & Institute, Beijing 100142, China; (X.-H.T.); (X.-L.W.)
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Xu F, Wu J, Hu Y, Chu C, Liu W, Li X, Zheng W, Yang W, Zhao B, Guo J, Wang Z, Jia Y, Xiao W. Mechanisms of action underlying the effect of Tongsaimai on wound healing based on experimental and network pharmacology. JOURNAL OF ETHNOPHARMACOLOGY 2023; 311:116451. [PMID: 37031824 DOI: 10.1016/j.jep.2023.116451] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 02/23/2023] [Accepted: 03/31/2023] [Indexed: 06/19/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Tongsaimai (TSM) is a traditional Chinese medicine that has several therapeutic qualities, including anti-inflammatory, anti-oxidative, and anti-vasculitis effects. However, its impacts and underlying mechanisms on wound healing remain unclear. AIM OF THE STUDY The aim of our study was to evaluate TSM for its pro-healing effect and the relevant mechanisms using both experimental validation and network pharmacology analysis. MATERIALS AND METHODS The components of TSM were detected by high-performance liquid chromatography combined with diode array detector (HPLC-DAD). Skin wounds with a diameter of 4 mm were created on the backs of mice, after which, topical treatments of 2.5-10% TSM were applied onto the lesions once daily for either 2 or 7 days. Then, the wound tissues were collected to determine the impacts of TSM on collagen deposition, epithelial cell proliferation, oxidative stress, inflammation, and angiogenesis. Moreover, the effects of TSM (0.5-2 mg/mL) on the cell viability of HUVECs and HaCaT cells were evaluated. RESULTS A total of 11 components in TSM were identified by HPLC-DAD. TSM was found to enhance the rate of wound contraction and increase epithelial thickness and collagen deposition during the healing process. In addition, TSM increased SOD activity and downregulated MDA and IL-1β levels in the wound tissues. Immunofluorescence analysis further indicated an increased expression of Ki67, CD31, and VEGF in wound tissues following TSM administration. Results of the network pharmacology analysis revealed that multiple pathways including VEGF, PI3K/Akt, and MAPK pathways were involved in the pharmacological actions of TSM on wound healing. Accordantly, in vitro experiments revealed that TSM promoted the proliferation of HUVECs and HaCaT cells while activating the PI3K/Akt pathway. CONCLUSIONS Our results suggest that TSM may serve as a therapeutic medication to improve wound healing by employing multiple regulatory mechanisms that affect proliferation, angiogenesis, collagen deposition, oxidative stress, and inflammation.
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Affiliation(s)
- Fanxing Xu
- Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, 222001, China; Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Jingxian Wu
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yumei Hu
- Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, 222001, China
| | - Chun Chu
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Wenjun Liu
- Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, 222001, China
| | - Xiang Li
- School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Wen Zheng
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Weishuo Yang
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Boyan Zhao
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Jiangxue Guo
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Zhenzhong Wang
- Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, 222001, China
| | - Ying Jia
- Faculty of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Wei Xiao
- Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, 222001, China.
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11
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Cui MY, Yi X, Zhu DX, Wu J. Aberrant lipid metabolism reprogramming and immune microenvironment for gastric cancer: a literature review. Transl Cancer Res 2022; 10:3829-3842. [PMID: 35116681 PMCID: PMC8797372 DOI: 10.21037/tcr-21-655] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 07/05/2021] [Indexed: 12/15/2022]
Abstract
Objective We summarize the aberrant lipid metabolism disorders associated with enzyme activity and expression changes and related immune microenvironment for gastric cancer. Background Gastric cancer is a malignant tumor of the primary digestive system with high incidence, poor prognosis characterized by extensive metastasis and poor effect with radiotherapy and chemotherapy. One of the most important metabolic characteristics of cancer cells is lipid metabolism reprogramming to adapt to the tumor micro-environment. Methods The focus of research in recent years has also been on lipid metabolism disorders, particularly aberrant metabolism of fatty acids (FAs) in gastric cancer cells, as well as an upregulation of the expression and activity of key enzymes in lipid metabolism. These changes remind us of the occurrence and development of gastric cancer. These metabolic changes are not unique to cancer cells. Changes in metabolic procedures also determine the function and viability of immune cells. In the immune microenvironment of gastric cancer, the metabolic competition and interaction between cancer cells and immune cells are not very clear, while a deeper understanding of the topic is critical to targeting the differential metabolic requirements of them that comprise an immune response to cancer offers an opportunity to selectively regulate immune cell function. Conclusions Recent research suggests that targeting metabolism is an emerging and potentially promising treatment strategy for gastric cancer patients. We need to explore it further.
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Affiliation(s)
- Meng-Ying Cui
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xing Yi
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Dan-Xia Zhu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Jun Wu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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12
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Matus MF, Malola S, Häkkinen H. Ligand Ratio Plays a Critical Role in the Design of Optimal Multifunctional Gold Nanoclusters for Targeted Gastric Cancer Therapy. ACS NANOSCIENCE AU 2021; 1:47-60. [PMID: 37102116 PMCID: PMC10125177 DOI: 10.1021/acsnanoscienceau.1c00008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Nanodrug delivery systems (NDDSs) based on water-soluble and atomically precise gold nanoclusters (AuNCs) are under the spotlight due to their great potential in cancer theranostics. Gastric cancer (GC) is one of the most aggressive cancers with a low early diagnosis rate, with drug therapy being the primary means to overcome its increasing incidence. In this work, we designed and characterized a set of 28 targeted nanosystems based on Au144(p-MBA)60 (p-MBA = para-mercaptobenzoic acid) nanocluster to be potentially employed as combination therapy in GC treatment. The proposed multifunctional AuNCs are functionalized with cytotoxic drugs (5-fluorouracil and epirubicin) or inhibitors of different signaling pathways (phosphatidylinositol 3-kinases (PI3K)/protein kinase B (Akt)/mammalian target of the rapamycin (mTOR), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor (HIF)) and RGD peptides as targeting ligands, and we studied the role of ligand ratio in their optimal structural conformation using peptide-protein docking and all-atom molecular dynamics (MD) simulations. The results reveal that the peptide/drug ratio is a crucial factor influencing the potential targeting ability of the nanosystem. The most convenient features were observed when the peptide amount was favored over the drug in most cases; however, we demonstrated that the system composition and the intermolecular interactions on the ligand shell are crucial for achieving the desired effect. This approach helps guide the experimental stage, providing essential information on the size and composition of the nanosystem at the atomic level for ligand tuning in order to increase the desired properties.
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13
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Wang L, Cheng L, Ma L, Ahmad Farooqi A, Qiao G, Zhang Y, Ye H, Liu M, Huang J, Yang X, Lin X, Cao S. Alnustone inhibits the growth of hepatocellular carcinoma via ROS- mediated PI3K/Akt/mTOR/p70S6K axis. Phytother Res 2021; 36:525-542. [PMID: 34847624 DOI: 10.1002/ptr.7337] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 10/28/2021] [Accepted: 11/03/2021] [Indexed: 01/05/2023]
Abstract
Alnustone, a diarylheptane compound, exhibits potent growth inhibition against hepatocellular carcinoma (HCC) BEL-7402 cells. However, the underlying mechanisms associated with its anticancer activity remain unknown. In the present study, we evaluated the anticancer effect of alnustone against several human cancers focused on HCC and the possible associated mechanisms. The results showed that alnustone significantly inhibited the growth of several cancer cells by CCK-8 assay. Alnustone markedly induced apoptosis and decreased mitochondrial membrane potential in BEL-7402 and HepG2 cells. Alnustone inhibited the expression of proteins related to apoptosis and PI3K/Akt/mTOR/p70S6K pathways and generated ROS production in BEL-7402 and HepG2 cells. Moreover, N-acetyl-L-cysteine (NAC, a ROS inhibitor) could significantly reverse the effects of alnustone on the growth inhibition of BEL-7402 and HepG2 cells and the expression of proteins related to apoptosis and PI3K/Akt/mTOR signaling pathway in HepG2 cells. Furthermore, alnustone significantly inhibited tumor growth of HepG2 xenografts, obviously induced apoptosis in the tumor tissues and improved the pathological condition of liver tissues of mice in vivo. The study provides evidence that alnustone is effective against HCC via ROS-mediated PI3K/Akt/mTOR/p70S6K pathway and the compound has the potential to be developed as a novel anticancer agent for the treatment of HCC clinically.
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Affiliation(s)
- Linlin Wang
- Department of Pharmacology, Southwest Medical University, Luzhou, Sichuan, China
| | - Li Cheng
- Department of Pharmacology, Southwest Medical University, Luzhou, Sichuan, China
| | - Li Ma
- Rizhao Hospital of Traditional Chinese Medicine, Rizhao, Shandong, China
| | - Ammad Ahmad Farooqi
- Department of Molecular Oncology, Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan
| | - Gan Qiao
- Department of Pharmacology, Southwest Medical University, Luzhou, Sichuan, China
| | - Yuxi Zhang
- Department of Pharmacology, Southwest Medical University, Luzhou, Sichuan, China
| | - Hanlin Ye
- Department of Pharmacology, Southwest Medical University, Luzhou, Sichuan, China
| | - Minghua Liu
- Department of Pharmacology, Southwest Medical University, Luzhou, Sichuan, China
| | - Jianlin Huang
- Department of Pharmacology, Southwest Medical University, Luzhou, Sichuan, China
| | - Xiaohui Yang
- Department of Pharmacology, Southwest Medical University, Luzhou, Sichuan, China
| | - Xiukun Lin
- Department of Pharmacology, Southwest Medical University, Luzhou, Sichuan, China.,Delisi Group Co. Ltd., Zhucheng, Shandong, China
| | - Shousong Cao
- Department of Pharmacology, Southwest Medical University, Luzhou, Sichuan, China
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14
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Liu M, Yang P, Fu D, Gao T, Deng X, Shao M, Liao J, Jiang H, Li X. Allicin protects against myocardial I/R by accelerating angiogenesis via the miR-19a-3p/PI3K/AKT axis. Aging (Albany NY) 2021; 13:22843-22855. [PMID: 34607973 PMCID: PMC8544308 DOI: 10.18632/aging.203578] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 09/07/2021] [Indexed: 12/19/2022]
Abstract
Objectives: Allicin is an allyl 2-propenethiosulfinate or diallyl thiosulfinate acid with cardioprotective effects in myocardial ischemia/reperfusion (MI/R) injury. This study aims to examine the underlying mechanism by which Allicin protects against MI/R. Methods: C57BL6 mice were subjected to either sham or MI/R surgery, and mice in the Allicin group were injected with Allicin (5 mg/ml) before the induction of ischemia. The cardiac function and histopathology of experimental mice were evaluated by ultrasound quantification and Masson staining. We next measured the capillary angiogenesis of the peri-infarct area by Masson staining and immunohistochemical staining. The miRNA microarray was carried out to examine the expressed miRNAs in MI/R tissues and corresponding normal tissues. Real-time quantitative polymerase chain reaction (q-PCR) was performed to validate the selected miRNA-19α-3p gene expression. Besides, we evaluated the myocardial lactate dehydrogenase and COX-2 by immunofluorescence staining. The western blot analysis was used to evaluate the protein levels of p-AKT, p-PI3K, p-mTOR, COX-2, and VEGF protein in the Allicin and Model group. In vitro study, LPS stimulated Tie2 expressing macrophages were cultured in an ischemic buffer. We evaluated the accumulation of VEGF by fura-2/AM fluorescence. Besides, Western blotting was performed to examine the protein levels of p-PI3K, p-AKT, p-mTOR, VEGF, COX2, and MMP2. The PI3K inhibitor was applied to investigate whether Allicin-induced myocardial ischemia-reperfusion injury protection is mediated via the PI3K/AKT pathway. And the miR-19α-3p mimic/inhibitor were transfected to promote/inhibit the expression of miR-19a-3p for verifying the regulation of miR-19a-3p on PI3K pathway. Results: Allicin pretreatment significantly improved I/R-induced cardiac function damage. Furthermore, Allicin could repress cardiac fibrosis, as evidenced by reduced areas of cardiac fibrosis. Allicin’s effect on the MI/R was associated with increased capillary angiogenesis. Microarray analysis exposed that miR-19a-3p down-regulated PIK3CA (PI3K) expression by directly targeting the PIK3CA gene. The regulation of the angiogenesis pathway and gene miRNA-19a-3p might affect the Allicin-induced MI/R protection. Immunofluorescence staining revealed that COX-2 and myocardial lactate dehydrogenase were significantly increased after Allicin treatment. Furthermore, western blot analysis demonstrated that p-AKT, p-PI3K, p-mTOR, COX-2, and VEGF protein levels were also increased in the Allicin group. In vitro study, the protein levels of p-PI3K, p-AKT, p-mTOR, VEGF, COX2, and MMP2 were significantly increased in the Allicin-treated Tie2 expressing macrophages. These effects were partially reversed by PI3K inhibitor (Wortmannin) treatment. MiR-19α-3p plays an important role in myocardial I/R injury. It could regulate the activity of the PI3K-AKT pathway. And inhibition of miR-19a-3p promoted angiogenesis by regulating PI3K/AKT pathway. Conclusions: Allicin pretreatment protects against myocardial I/R and activating the miR-19a-3p/PI3K/AKT pathway.
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Affiliation(s)
- Mengru Liu
- Graduate School of Peking Union Medical College, Beijing 100730, China.,Department of Integrative Medicine Cardiology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Peng Yang
- Department of Integrative Medicine Cardiology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Dongliang Fu
- Department of Integrative Medicine Cardiology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Tong Gao
- Graduate School of Peking Union Medical College, Beijing 100730, China.,Department of Integrative Medicine Cardiology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Xinyi Deng
- Department of Integrative Medicine Cardiology, China-Japan Friendship Hospital, Beijing 100029, China.,Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Mingjing Shao
- Department of Integrative Medicine Cardiology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Jiangquan Liao
- Department of Integrative Medicine Cardiology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Hong Jiang
- Department of Integrative Medicine Cardiology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Xianlun Li
- Graduate School of Peking Union Medical College, Beijing 100730, China.,Department of Integrative Medicine Cardiology, China-Japan Friendship Hospital, Beijing 100029, China.,Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
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15
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Mardanshahi A, Gharibkandi NA, Vaseghi S, Abedi SM, Molavipordanjani S. The PI3K/AKT/mTOR signaling pathway inhibitors enhance radiosensitivity in cancer cell lines. Mol Biol Rep 2021; 48:1-14. [PMID: 34357550 DOI: 10.1007/s11033-021-06607-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 07/29/2021] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Radiotherapy is one of the most common types of cancer treatment modalities. Radiation can affect both cancer and normal tissues, which limits the whole delivered dose. It is well documented that radiation activates phosphatidylinositol 3-kinase (PI3K) and AKT signaling pathway; hence, the inhibition of this pathway enhances the radiosensitivity of tumor cells. The mammalian target of rapamycin (mTOR) is a regulator that is involved in autophagy, cell growth, proliferation, and survival. CONCLUSION The inhibition of mTOR as a downstream mediator of the PI3K/AKT signaling pathway represents a vital option for more effective cancer treatments. The combination of PI3K/AKT/mTOR inhibitors with radiation can increase the radiosensitivity of malignant cells to radiation by autophagy activation. Therefore, this review aims to discuss the impact of such inhibitors on the cell response to radiation.
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Affiliation(s)
- Alireza Mardanshahi
- Department of Radiology and Nuclear Medicine, Faculty of Medicine, Cardiovascular Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Nasrin Abbasi Gharibkandi
- Department of Radiopharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Samaneh Vaseghi
- Department of Chemistry, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Seyed Mohammad Abedi
- Department of Radiology and Nuclear Medicine, Faculty of Medicine, Cardiovascular Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Sajjad Molavipordanjani
- Department of Radiology and Nuclear Medicine, Faculty of Medicine, Cardiovascular Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
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16
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Danesh Pazhooh R, Rahnamay Farnood P, Asemi Z, Mirsafaei L, Yousefi B, Mirzaei H. mTOR pathway and DNA damage response: A therapeutic strategy in cancer therapy. DNA Repair (Amst) 2021; 104:103142. [PMID: 34102579 DOI: 10.1016/j.dnarep.2021.103142] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/26/2021] [Accepted: 05/31/2021] [Indexed: 10/21/2022]
Abstract
The mammalian target of rapamycin (mTOR) is a conserved serine/threonine-protein kinase, comprising two subunit protein complexes: mTORC1 and mTORC2. In response to insult and cancer, the mTOR pathway plays a crucial role in regulating growth, metabolism, cell survival, and protein synthesis. Key subunits of mTORC1/2 catalyze the phosphorylation of various molecules, including eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), ribosomal protein S6 kinase β-1 (S6K1). The DNA damage response (DDR) maintains genomic stability and provides an opportunity for treating tumors with defects caused by DNA damaging agents. Many mTOR inhibitors are utilized for the treatment of cancers. However, several clinical trials are still assessing the efficacy of mTOR inhibitors. This paper discusses the role of the mTOR signaling pathway and its regulators in developing cancer. In the following, we will review the interaction between DDR and mTOR signaling and the innovative therapies applied in preclinical and clinical trials for treating cancers.
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Affiliation(s)
| | | | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Liaosadat Mirsafaei
- Department of Cardiology, Ramsar Campus, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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17
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Xu T, Rao T, Yu WM, Ning JZ, Yu X, Zhu SM, Yang K, Bai T, Cheng F. Upregulation of NFKBIZ affects bladder cancer progression via the PTEN/PI3K/Akt signaling pathway. Int J Mol Med 2021; 47:109. [PMID: 33907827 PMCID: PMC8057294 DOI: 10.3892/ijmm.2021.4942] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 03/26/2021] [Indexed: 12/14/2022] Open
Abstract
NF‑κB inhibitor ζ (NFKBIZ), a member of the IκB family that interacts with NF‑κB, has been reported to be an important regulator of inflammation, cell proliferation and survival. However, the role of NFKBIZ in bladder cancer (BC) remains unknown. The present study aimed to investigate the functions of NFKBIZ in BC. First, the expression levels of NFKBIZ and the associations between NFKBIZ expression and the clinical survival of patients were determined using BC tissue samples, BC cell lines and datasets from different databases. Two BC cell lines (T24 and 5637) were selected to overexpress NFKBIZ, and the proliferative, migratory and invasive abilities of cells were determined; additionally, tumor growth following transplantation in in vivo mouse models was analyzed using T24 cells overexpressing NFKBIZ. Subsequently, the association between NFKBIZ and PTEN was determined using data from databases and immunohistochemistry analysis of clinical and nude mice tumor tissues. Finally, the interactions between NFKBIZ, PTEN and the downstream PI3K/AKT/mTOR signaling pathway were evaluated using western blotting. In conclusion, the present results indicated that NFKBIZ expression was low in BC, and NFKBIZ inhibited the proliferation of BC cells through the PTEN/PI3K/Akt signaling pathway, suggesting that NFKBIZ may represent a novel prognostic biomarker in BC and may provide a potential therapeutic tumor‑associated antigen for BC.
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Affiliation(s)
- Tao Xu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Ting Rao
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Wei-Ming Yu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Jin-Zhuo Ning
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Xi Yu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Shao-Ming Zhu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Kang Yang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Tao Bai
- Department of Urology, Wuhan No. 1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430060, P.R. China
| | - Fan Cheng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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18
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Baghery Saghchy Khorasani A, Pourbagheri-Sigaroodi A, Pirsalehi A, Safaroghli-Azar A, Zali MR, Bashash D. The PI3K/Akt/mTOR signaling pathway in gastric cancer; from oncogenic variations to the possibilities for pharmacologic interventions. Eur J Pharmacol 2021; 898:173983. [PMID: 33647255 DOI: 10.1016/j.ejphar.2021.173983] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 02/13/2021] [Accepted: 02/23/2021] [Indexed: 12/24/2022]
Abstract
Genetic and epigenetic alterations have been under concentrated investigations for many years in order to unearth the molecules regulating human cancer pathogenesis. However, the identification of a wide range of dysregulated genes and their protein products has raised a question regarding how the results of this large collection of alterations could converge into a formation of one malignancy. The answer may be found in the signaling cascades that regulate the survival and metabolism of the cells. Aberrancies of each participant molecule of such cascades may well result in augmented viability and unlimited proliferation of cancer cells. Among various signaling pathways, the phosphatidylinositol-3-kinase (PI3K) axis has been shown to be activated in about one-third of human cancers. One of the malignancies that is mostly affected by this axis is gastric cancer (GC), one of the most fatal cancers worldwide. In the present review, we aimed to illustrate the significance of the PI3K/Akt/mTOR axis in the pathogenesis of GC and also provided a wide perspective about the application of the inhibitors of this axis in the therapeutic strategies of this malignancy.
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Affiliation(s)
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Pirsalehi
- Department of Internal Medicine, School of Medicine, Ayatollah Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ava Safaroghli-Azar
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, 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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19
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Rashid MM, Lee H, Jung BH. Evaluation of the antitumor effects of PP242 in a colon cancer xenograft mouse model using comprehensive metabolomics and lipidomics. Sci Rep 2020; 10:17523. [PMID: 33067464 PMCID: PMC7568555 DOI: 10.1038/s41598-020-73721-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 09/22/2020] [Indexed: 01/16/2023] Open
Abstract
PP242, an inhibitor of mechanistic target of rapamycin (mTOR), displays potent anticancer effects against various cancer types. However, the underlying metabolic mechanism associated with the PP242 effects is not clearly understood. In this study, comprehensive metabolomics and lipidomics investigations were performed using ultra-high-performance chromatography-Orbitrap-mass spectrometry (UHPLC-Orbitrap-MS) in plasma and tumor tissue to reveal the metabolic mechanism of PP242 in an LS174T cell-induced colon cancer xenograft mouse model. After 3 weeks of PP242 treatment, a reduction in tumor size and weight was observed without any critical toxicities. According to results, metabolic changes due to the effects of PP242 were not significant in plasma. In contrast, metabolic changes in tumor tissues were very significant in the PP242-treated group compared to the xenograft control (XC) group, and revealed that energy and lipid metabolism were mainly altered by PP242 treatment like other cancer inhibitors. Additionally, in this study, it was discovered that not only TCA cycle but also fatty acid β-oxidation (β-FAO) for energy metabolism was inhibited and clear reduction in glycerophospholipid was observed. This study reveals new insights into the underlying anticancer mechanism of the dual mTOR inhibitor PP242, and could help further to facilitate the understanding of PP242 effects in the clinical application.
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Affiliation(s)
- Md Mamunur Rashid
- Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, 02792, South Korea.,Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology (UST), Seoul, 02792, South Korea
| | - Hyunbeom Lee
- Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, 02792, South Korea
| | - Byung Hwa Jung
- Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, 02792, South Korea. .,Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology (UST), Seoul, 02792, South Korea.
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20
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Lin HY, Kuei CH, Lee HH, Lin CH, Zheng JQ, Chiu HW, Chen CL, Lin YF. The Gαh/phospholipase C-δ1 interaction promotes autophagosome degradation by activating the Akt/mTORC1 pathway in metastatic triple-negative breast cancer. Aging (Albany NY) 2020; 12:13023-13037. [PMID: 32615541 PMCID: PMC7377847 DOI: 10.18632/aging.103390] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 05/03/2020] [Indexed: 02/07/2023]
Abstract
Lung metastasis (LM) is commonly found in triple-negative breast cancer (TNBC); however, the molecular mechanism underlying TNBC metastasis to lungs remains largely unknown. We thus aimed to uncover a possible mechanism for the LM of TNBC. Here we show that the phosphorylation of Akt and mTORC1 was positively but the autophagy activity was negatively correlated with endogenous Gαh levels and cell invasion ability in TNBC cell lines. Whereas the knockdown of Gαh, as well as blocking its binding with PLC-δ1 by a synthetic peptide inhibitor, in the highly invasive MDA-MB231 cells dramatically suppressed Akt/mTORC1 phosphorylation and blocked autophagosome degradation, the overexpression of Gαh in the poorly invasive HCC1806 cells enhanced Akt/mTORC1 phosphorylation but promoted autophagosome degradation. The pharmaceutical inhibition of autophagy initiation by 3-methyladenine was found to rescue the cell invasion ability and LM potential of Gαh-silenced MDA-MB231 cells. In contrast, the inhibition of mTORC1 activity by rapamycin suppressed autophagosome degradation but mitigated the cell invasion ability and LM potential of Gαh-overexpressing HCC1806 cells. These findings demonstrate that the induction of autophagy activity or the inhibition of Akt-mTORC1 axis provides a useful strategy to combat the Gαh/PLC-δ1-driven LM of TNBC.
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Affiliation(s)
- Hui-Yu Lin
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Breast Surgery and General Surgery, Division of Surgery, Cardinal Tien Hospital, Xindian District, New Taipei, Taiwan
| | - Chia-Hao Kuei
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Urology, Division of Surgery, Cardinal Tien Hospital, Xindian District, New Taipei, Taiwan
| | - Hsun-Hua Lee
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan.,Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Neurology, Vertigo and Balance Impairment Center, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
| | - Che-Hsuan Lin
- Department of Otolaryngology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Otolaryngology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
| | - Jing-Quan Zheng
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Critical Care Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
| | - Hui-Wen Chiu
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
| | - Chi-Long Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
| | - Yuan-Feng Lin
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
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21
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Cai C, Dang W, Liu S, Huang L, Li Y, Li G, Yan S, Jiang C, Song X, Hu Y, Gu J. Anthrax toxin receptor 1/tumor endothelial marker 8 promotes gastric cancer progression through activation of the PI3K/AKT/mTOR signaling pathway. Cancer Sci 2020; 111:1132-1145. [PMID: 31977138 PMCID: PMC7156833 DOI: 10.1111/cas.14326] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 12/25/2019] [Accepted: 01/06/2020] [Indexed: 01/18/2023] Open
Abstract
Anthrax toxin receptor 1 (ANTXR1), a type I transmembrane protein, is one of the receptors that facilitates the entrance of anthrax toxin into cells. Previous studies have confirmed the pivotal role of ANTXR1 in progression and tumorigenesis of diverse cancer types. However, the biological function of ANTXR1 in gastric cancer (GC) is still unknown. The present study aimed to investigate the role of ANTXR1 in GC and illuminate the potential molecular mechanisms. Bioinformatics analysis found that ANTXR1 expression was significantly upregulated in GC tissue and its overexpression was associated with poor prognosis of GC patients. Moreover, we confirmed the upregulation of ANTXR1 in GC cell lines and GC tissue by quantitative PCR, western blot analysis, and immunohistochemical analysis. Additionally, high protein expression level of ANTXR1 was positively associated with several clinicopathological parameters in GC patients. In our study, a series of in vitro and in vivo assays were undertaken through strategies of loss/gain-of-function and rescue assays. Consequently, our results indicated that ANTXR1 induced proliferation, cell cycle progression, invasion and migration, and tumorigenicity and induced suppressed apoptosis in GC. Mechanistic investigation indicated that ANTXR1 exerted its promoting effects on GC through activation of the PI3K/AKT/mTOR signaling pathway. In conclusion, our findings suggested that ANTXR1 plays a crucial role in the development and progression of GC and could serve as a novel prognostic biomarker and potential therapeutic target for GC.
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Affiliation(s)
- Chen Cai
- Department of General SurgeryXinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Biliary Tract Disease ResearchShanghaiChina
| | - Wei Dang
- Department of General SurgeryXinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Biliary Tract Disease ResearchShanghaiChina
| | - Shilei Liu
- Department of General SurgeryXinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Biliary Tract Disease ResearchShanghaiChina
| | - Ling Huang
- Department of General SurgeryXinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Biliary Tract Disease ResearchShanghaiChina
| | - Yang Li
- Department of General SurgeryXinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Biliary Tract Disease ResearchShanghaiChina
| | - Guoqiang Li
- Department of General SurgeryXinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Biliary Tract Disease ResearchShanghaiChina
| | - Siyuan Yan
- Department of General SurgeryXinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Biliary Tract Disease ResearchShanghaiChina
| | - Chengkai Jiang
- Department of General SurgeryXinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Biliary Tract Disease ResearchShanghaiChina
| | - Xiaoling Song
- Department of General SurgeryXinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Biliary Tract Disease ResearchShanghaiChina
| | - Yunping Hu
- Department of General SurgeryXinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Biliary Tract Disease ResearchShanghaiChina
| | - Jun Gu
- Department of General SurgeryXinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Biliary Tract Disease ResearchShanghaiChina
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22
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Jiang C, Ma Z, Zhang G, Yang X, Du Q, Wang W. CSNK2A1 Promotes Gastric Cancer Invasion Through the PI3K-Akt-mTOR Signaling Pathway. Cancer Manag Res 2019; 11:10135-10143. [PMID: 31819646 PMCID: PMC6897054 DOI: 10.2147/cmar.s222620] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 11/12/2019] [Indexed: 12/24/2022] Open
Abstract
Objective Casein kinase 2 a1 (CSNK2A1) has been shown to be involved in tumorigenesis by enhancing several oncogenic signaling pathways in various cancers. However, the function and mechanism of CSNK2A1 in gastric cancer remain unclear, and this study aimed to elucidate the role of CSNK2A1 in gastric cancer. Methods CSNK2A1 expression was assessed by Western blot and qPCR in four gastric cancer (GC) cell lines and one normal gastric epithelial cell line. Stable cancer cell lines with CSNK2A1 gene overexpression or knockdown were established to investigate the function and mechanism of CSNK2A1 in GC cells. Results CSNK2A1 expression was higher in GC cells than in normal gastric epithelial cells. Stable overexpression of CSNK2A1 in SNU216 cells significantly increased cellular proliferation, invasion, and migration. Silencing CSNK2A1 expression in SGC-790 cells effectively inhibited its oncogenic function. We further verified that epithelial-mesenchymal transition (EMT) was affected by CSNK2A1 and that CSNK2A1 promotes GC cell invasion through the PI3K-Akt-mTOR signaling pathway. Conclusion Our findings suggested that CSNK2A1 plays important oncogenic roles in GC invasion via EMT and the PI3K-Akt-mTOR signaling pathway and that CSNK2A1 may serve as a novel prognostic and/or therapeutic target in GC.
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Affiliation(s)
- Chao Jiang
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, People's Republic of China.,Departments of Oncology, Affiliated Hospital of Shandong Academy of Medical Sciences, Shandong First Medical University, Jinan, Shandong 250031, People's Republic of China
| | - Zhenghong Ma
- Departments of Oncology, Affiliated Hospital of Shandong Academy of Medical Sciences, Shandong First Medical University, Jinan, Shandong 250031, People's Republic of China
| | - Guoan Zhang
- Forensic Science Center, Jining Medical University, Jining, Shandong 272067, People's Republic of China.,Cancer Pathology Institute, Jining Medical University, Jining, Shandong 272000, People's Republic of China
| | - Xigui Yang
- Departments of Oncology, Affiliated Hospital of Shandong Academy of Medical Sciences, Shandong First Medical University, Jinan, Shandong 250031, People's Republic of China
| | - Qin Du
- Departments of Oncology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, People's Republic of China
| | - Weibo Wang
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, People's Republic of China
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23
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Notch1 and PI3K/Akt signaling blockers DAPT and LY294002 coordinately inhibit metastasis of gastric cancer through mutual enhancement. Cancer Chemother Pharmacol 2019; 85:309-320. [PMID: 31732769 DOI: 10.1007/s00280-019-03990-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 11/06/2019] [Indexed: 02/07/2023]
Abstract
PURPOSE Blockade of either Notch1 or PI3K/Akt pathway inhibits metastasis of gastric cancer. However, whether blockade of both pathways coordinately exerts such an effect remains unknown. In this study, we aimed to investigate the effects of combined treatment with Notch1 signaling blocker DAPT and PI3K/Akt signal blocker LY294002 on metastasis of gastric cancer. METHODS Notch intracellular domain (NICD) and phosphorylated Akt (p-Akt) levels in gastric cancer tissues and their adjacent normal tissue samples and gastric cancer SGC7901 and AGS cells and normal GES-1 cells were determined using immunohistochemistry and Western blotting. The effects of combined DAPT and LY294002 on metastasis of gastric cancer were evaluated by examining migration and invasion potential of SGC7901 cells using wound healing and transwell assays, determining changes in the levels of epithelial-mesenchymal transition biomarkers and MMP-9, Notch1, HES1, and phosphorylation of Akt in gastric cancer SGC7901 cells and/or AGS cells in vitro using Western blotting, and metastasis of gastric cancer to lungs in BALB/c nude mice after treatment. RESULTS NICD and p-Akt levels were significantly higher in gastric cancer tissues and SGC7901 and AGS cells than those in the normal control and GES-1 cells. Migration and invasion potential of SGC7901 cells, EMT biomarkers and MMP-9 in SGC7901 cells, and metastasis of gastric cancer to lungs in mice were coordinately inhibited by DAPT and LY294002. In addition, DAPT and LY294002 coordinately inhibited the levels of Notch1, HES1, and p-Akt in gastric cancer cells. CONCLUSION DAPT and LY294002 coordinately inhibited metastasis of gastric cancer through mutual enhancement.
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24
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Zhang Y, Zhou X, Cheng L, Wang X, Zhang Q, Zhang Y, Sun S. PRKAA1 Promotes Proliferation and Inhibits Apoptosis of Gastric Cancer Cells Through Activating JNK1 and Akt Pathways. Oncol Res 2019; 28:213-223. [PMID: 31558185 PMCID: PMC7851536 DOI: 10.3727/096504019x15668125347026] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
PRKAA1 (protein kinase AMP-activated catalytic subunit α 1) is a catalytic subunit of AMP-activated protein kinase (AMPK), which plays a key role in regulating cellular energy metabolism through phosphorylation, and genetic variations in the PRKAA1 have been found to be associated with gastric cancer risk. However, the effect and underlying molecular mechanism of PRKAA1 on gastric cancer tumorigenesis, especially the proliferation and apoptosis, are not fully understood. Our data showed that PRKAA1 is highly expressed in BGC-823 and MKN45 cells and is expressed low in SGC-7901 and MGC-803 cells in comparison with the other gastric cancer cells. PRKAA1 downregulation by shRNA or treatment of AMPK inhibitor compound C significantly inhibited proliferation as well as promoted cell cycle arrest and apoptosis of BGC-823 and MKN45 cells. Moreover, the expression of PCNA and Bcl-2 and the activity of JNK1 and Akt signaling were also reduced in BGC-823 and MKN45 cells after PRKAA1 downregulation. In vivo experiments demonstrated that tumor growth in nude mice was significantly inhibited after PRKAA1 silencing. Importantly, inactivation of JNK1 or Akt signaling pathway significantly inhibited PRKAA1 overexpression-induced increased cell proliferation and decreased cell apoptosis in MGC-803 cells. In conclusion, our findings suggest that PRKAA1 increases proliferation and restrains apoptosis of gastric cancer cells through activating JNK1 and Akt pathways.
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Affiliation(s)
- Yangmei Zhang
- Department of Oncology, Xuzhou Central Hospital, Xuzhou Medical UniversityXuzhouP.R. China
| | - Xichang Zhou
- Department of Intervention, Xuzhou Central Hospital, Xuzhou Medical UniversityXuzhouP.R. China
| | - Long Cheng
- Department of Intervention, Xuzhou Central Hospital, Xuzhou Medical UniversityXuzhouP.R. China
| | - Xiang Wang
- Department of Oncology, Xuzhou Central Hospital, Xuzhou Medical UniversityXuzhouP.R. China
| | - Qinglin Zhang
- Department of Central Laboratory, Xuzhou Central Hospital, Xuzhou Medical UniversityXuzhouP.R. China
| | - Youwei Zhang
- Department of Oncology, Xuzhou Central Hospital, Xuzhou Medical UniversityXuzhouP.R. China
| | - Sanyuan Sun
- Department of Oncology, Xuzhou Central Hospital, Xuzhou Medical UniversityXuzhouP.R. China
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25
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Zhang F, Ma C. Kaempferol suppresses human gastric cancer SNU-216 cell proliferation, promotes cell autophagy, but has no influence on cell apoptosis. ACTA ACUST UNITED AC 2019; 52:e7843. [PMID: 30785478 PMCID: PMC6376319 DOI: 10.1590/1414-431x20187843] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Accepted: 11/19/2018] [Indexed: 02/06/2023]
Abstract
Gastric cancer remains a serious threat to human health worldwide. Kaempferol is a plant-derived flavonoid compound with a wide range of pharmacological activities. This study aimed to investigate the effects of kaempferol on gastric cancer SNU-216 cell proliferation, apoptosis, and autophagy, as well as underlying potential mechanisms. Viability, proliferation, and apoptosis of SNU-216 cells after kaempferol treatment were evaluated using cell counting kit-8 assay, 5-btomo-2′-deoxyuridine incorporation assay, and annexin V-FITC/PI staining, respectively. Quantitative reverse transcription PCR was performed to measure the mRNA expressions of cyclin D1 and microRNA-181a (miR-181a) in SNU-216 cells. Cell transfection was used to down-regulate the expression of miR-181a. The protein expression levels of cyclin D1, bcl-2, bax, caspase 3, caspase 9, autophagy-related gene 7, microtubule-associated protein 1 light chain 3-I (LC3-I), LC3-II, Beclin 1, p62, mitogen-activated protein kinase (MAPK), extracellular regulated protein kinases (ERK), and phosphatidylinositol 3 kinase (PI3K) in SNU-216 cells were detected using western blotting. Results showed that kaempferol significantly suppressed SNU-216 cell viability and proliferation but had no influence on cell apoptosis. Further results suggested that kaempferol significantly induced SNU-216 cell autophagy. The expression of miR-181a in SNU-216 cells after kaempferol treatment was enhanced. Kaempferol significantly inactivated MAPK/ERK and PI3K pathways in SNU-216 cells. Suppression of miR-181a significantly reversed the kaempferol-induced MAPK/ERK and PI3K pathways inactivation in SNU-216 cells. This research demonstrated that kaempferol suppressed proliferation and promoted autophagy of human gastric cancer SNU-216 cells by up-regulating miR-181a and inactivating MAPK/ERK and PI3K pathways.
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Affiliation(s)
- Fan Zhang
- Teaching and Research Department of Diagnostics, Jining Medical University, Jining, China
| | - Cuimei Ma
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining, China
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26
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Tian T, Li X, Zhang J. mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy. Int J Mol Sci 2019; 20:ijms20030755. [PMID: 30754640 PMCID: PMC6387042 DOI: 10.3390/ijms20030755] [Citation(s) in RCA: 421] [Impact Index Per Article: 70.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 01/28/2019] [Accepted: 02/01/2019] [Indexed: 12/12/2022] Open
Abstract
The mammalian or mechanistic target of rapamycin (mTOR) pathway plays a crucial role in regulation of cell survival, metabolism, growth and protein synthesis in response to upstream signals in both normal physiological and pathological conditions, especially in cancer. Aberrant mTOR signaling resulting from genetic alterations from different levels of the signal cascade is commonly observed in various types of cancers. Upon hyperactivation, mTOR signaling promotes cell proliferation and metabolism that contribute to tumor initiation and progression. In addition, mTOR also negatively regulates autophagy via different ways. We discuss mTOR signaling and its key upstream and downstream factors, the specific genetic changes in the mTOR pathway and the inhibitors of mTOR applied as therapeutic strategies in eight solid tumors. Although monotherapy and combination therapy with mTOR inhibitors have been extensively applied in preclinical and clinical trials in various cancer types, innovative therapies with better efficacy and less drug resistance are still in great need, and new biomarkers and deep sequencing technologies will facilitate these mTOR targeting drugs benefit the cancer patients in personalized therapy.
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Affiliation(s)
- Tian Tian
- College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China.
| | - Xiaoyi Li
- College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China.
| | - Jinhua Zhang
- College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China.
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27
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Yu JH, Chen L, Yu JY, Luo HQ, Wang L. PI3K-PKB-mTOR hyperactivation in relation to nasopharyngeal carcinoma progression and prognosis. J Cell Biochem 2018; 120:10186-10194. [PMID: 30582216 DOI: 10.1002/jcb.28303] [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: 04/16/2018] [Accepted: 11/28/2018] [Indexed: 12/27/2022]
Abstract
Nasopharyngeal carcinoma (NPC) has a unique and complex etiology, which is not completely understood. The aim of this study is to investigate the expression patterns of phosphatidylinositol 3-kinase (PI3K), protein kinase B (PKB), and mammalian target of rapamycin (mTOR) proteins in patients with NPC and their relationship with NPC progression and prognosis. Between January 2008 and March 2010, PI3K, PKB, and mTOR protein expressions were detected using immunohistochemistry among 119 patients with NPC and 30 healthy people. A 5-year follow-up was conducted for all patients. Correlations of PI3K, PKB, and mTOR proteins with the clinicopathological features and prognosis of NPC were evaluated using Spearman's rank correlation coefficient and Kaplan-Meier curve. Cox's regression analysis was performed to analyze the risk factors for the prognosis of NPC. First, PI3K, PKB, and mTOR were highly expressed in patients with NPC. The expressions of PI3K, PKB, and mTOR proteins were associated with T stage, N stage, clinical stage, relapse, and distant metastasis. Meanwhile, PI3K is positively correlated with PKB and PKB is positively correlated with mTOR in NPC. Higher PI3K, PKB, and mTOR protein expressions were related to a shorter survival time and a lower survival rate in NPC. Cox regression analysis revealed that age, T stage, N stage, PI3K, PKB, and mTOR were independent risk factors for NPC patient survival. Altogether, our data suggest that overexpression of PI3K, PKB, and mTOR proteins is an important indicator of poor survival in NPC. In addition, inhibition of PI3K-PKB-mTOR signaling may also contribute to the development of new therapeutic strategies for NPC.
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Affiliation(s)
- Jian-Hua Yu
- Department of Oncology, Jiangxi Provincial People's Hospital, Nanchang, China
| | - Li Chen
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jian-Yong Yu
- Department of Pharmacy, Jiangxi Provincial People's Hospital, Nanchang, China
| | - Hong-Qiang Luo
- Department of ENT, Jiangxi Provincial People's Hospital, Nanchang, China
| | - Ling Wang
- Department of Oncology, Jiangxi Provincial People's Hospital, Nanchang, China
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28
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Lu Z, Xu A, Yuan X, Chen K, Wang L, Guo T. Anticancer effect of resibufogenin on gastric carcinoma cells through the phosphoinositide 3-kinase/protein kinase B/glycogen synthase kinase 3β signaling pathway. Oncol Lett 2018; 16:3297-3302. [PMID: 30127928 DOI: 10.3892/ol.2018.8979] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 10/24/2017] [Indexed: 01/20/2023] Open
Abstract
The aim of the present study was to investigate the anticancer effect of resibufogenin in gastric carcinoma cells through the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase 3β (GSK3β) signaling pathway. MGC-803 cells were treated with 0, 1, 2, 4 and 8 µM resibufogenin for 12, 24 and 48 h. Cell viability and apoptosis were measured using an MTT assay and annexin V staining. Caspase-3 and caspase-8 activity were identified using caspase-3 and caspase-8 activity kits and a variety of protein expression [B cell lymphoma (Bcl)-2, Bcl-2-associated X protein (Bax), cyclin D1, cyclin E, PI3K, phosphorylated AKT, phosphorylated GSK3β and β-catenin] were quantified using western blot analysis. It was revealed that resibufogenin effectively inhibited cell proliferation, and induced apoptosis and caspase-3 and caspase-8 activity in MGC-803 cells. Furthermore, treatment with resibufogenin effectively increased Bax/Bcl-2 expression, and suppressed cyclin D1, cyclin E, PI3K, phosphorylated AKT, phosphorylated GSK3β and β-catenin protein expression in MGC-803 cells. These results suggest that the anticancer effect of resibufogenin induces gastric carcinoma cell death through the PI3K/AKT/GSK3β signaling pathway, offering a novel view of the mechanism by which resibufogenin functions as an agent to treat gastric carcinoma.
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Affiliation(s)
- Zhen Lu
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Aman Xu
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Xiao Yuan
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Kaiwei Chen
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Likun Wang
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Tao Guo
- Department of General Surgery, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
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29
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Zhou X, Cheng Z, Chen H, Shi S, Wang X, Orang M, Zhao J. CASTOR1 suppresses the progression of lung adenocarcinoma and predicts poor prognosis. J Cell Biochem 2018; 119:10186-10194. [PMID: 30132978 DOI: 10.1002/jcb.27360] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Accepted: 06/26/2018] [Indexed: 12/28/2022]
Abstract
As a naturally occurring inhibitor of mammalian target of rapamycin (mTOR), accumulated evidence has confirmed that CASTOR1 plays a pivotal role in regulating the progression of human malignancies. However, the function of CASTOR1 in the development of lung adenocarcinoma is still unclear. Here we report that the expression of CASTOR1 is significantly reduced in lung adenocarcinoma cell lines as compared with that in normal lung epithelial cells. Cellular studies further revealed that ectopic CASTOR1 expression led to a significant suppression of the cellular proliferation, migration, and invasion of PC-9 cells. To further test the role of CASTOR1 in human patients with lung cancers, tumor tissues derived from lung cancer patients and paired adjacent normal lung tissues were collected for immunohistochemical, biochemical, and molecular biology analysis. Immunoblotting and real-time quantitative reverse transcription polymerase chain reaction analysis is revealed that CASTOR1 was significantly reduced in tumor tissues as compared with that in paired normal lung tissues. With immunostaining and retrospective analysis of pathological samples from lung cancer patients further revealed that expression of CASTOR1 was negatively correlated with smoking history, TNM stage, lymphnode metastasis, and distant metastasis. Furthermore, Kaplan-Meier survival analysis indicated that patients with low CASTOR1 expression levels had a significantly worse 5-year survival rate than those with high CASTOR1 expression. To further explore the molecular actions of CASTOR1 in lung cancer development, biochemical assays were performed and the results suggested that ectopic CASTOR1 expression resulted significant suppression of mTOR and downstream S6K phosphorylation, indicating that CASTOR1 might regulate the progression of lung adenocarcinoma by controlling mTOR activation. Thus, these findings demonstrated that CASTOR1 inhibits the tumorigenesis of lung adenocarcinoma cells and might serve as a potential therapeutic target or prognostic marker for human patients with lung adenocarcinoma.
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Affiliation(s)
- Xuefeng Zhou
- Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Zhenshun Cheng
- Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Hao Chen
- Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Shenqi Shi
- Department of Surgery, Dawu People's Hospital, China
| | - Xianguo Wang
- Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Matthew Orang
- Department of Physical Education & Human Performance, Central Connecticut State University, New Britain, Connecticut
| | - Jinping Zhao
- Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
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31
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Ji YM, Zhou XF, Zhang J, Zheng X, Li SB, Wei ZQ, Liu T, Cheng DL, Liu P, Song K, Tan T, Zhu H, Guo JL. DEPTOR suppresses the progression of esophageal squamous cell carcinoma and predicts poor prognosis. Oncotarget 2017; 7:14188-98. [PMID: 26893358 PMCID: PMC4924707 DOI: 10.18632/oncotarget.7420] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 01/29/2016] [Indexed: 01/14/2023] Open
Abstract
As a naturally occurring inhibitor of mTOR, accumulated evidence has suggested that DEPTOR plays a pivotal role in suppressing the progression of human malignances. However, the function of DEPTOR in the development of esophageal squamous cell carcinoma (ESCC) is still unclear. Here we report that the expression of DEPTOR is significantly reduced in tumor tissues derived from human patients with ESCC, and the downregulation of DEPTOR predicts a poor prognosis of ESCC patients. In addition, we found that the expression of DEPTOR negatively regulates the tumorigenic activities of ESCC cell lines (KYSE150, KYSE510 and KYSE190). Furthermore, ectopic DEPTOR expression caused a significant suppression of the cellular proliferation, migration and invasion of KYSE150 cells, which has the lowest expression level of DEPTOR in the three cell lines. Meanwhile, CRISPR/Cas9 mediated knockout of DEPTOR in KYSE-510 cells significantly promoted cellular proliferation, migration and invasion. In addition, in vivo assays further revealed that tumor growth was significantly inhibited in xenografts with ectopic DEPTOR expression as compared to untreated KYSE150 cells, and was markedly enhanced in DEPTOR knockout KYSE-510 cells. Biochemical studies revealed that overexpression of DEPTOR led to the suppression of AKT/mTOR pathway as evidenced by reduced phosphorylation of AKT, mTOR and downstream SGK1, indicating DEPTOR might control the progression of ESCC through AKT/mTOR signaling pathway. Thus, these findings, for the first time, demonstrated that DEPTOR inhibits the tumorigenesis of ESCC cells and might serve as a potential therapeutic target or prognostic marker for human patients with ESCC.
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Affiliation(s)
- Yan-Mei Ji
- Department of Intensive Care Unit, Taihe Hospital, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Xue-Feng Zhou
- Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Jun Zhang
- Department of Cardiothoracic Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Xiang Zheng
- Department of Intensive Care Unit, Taihe Hospital, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Sheng-Bao Li
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Zhi-Qiang Wei
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Tao Liu
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Dong-Liang Cheng
- Department of Cardiothoracic Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Ping Liu
- Department of Pathology, Taihe Hospital, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Kuncheng Song
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Tao Tan
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Hua Zhu
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Jia-Long Guo
- Department of Cardiothoracic Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, People's Republic of China
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Rashid MM, Lee H, Jung BH. Metabolite identification and pharmacokinetic profiling of PP242, an ATP-competitive inhibitor of mTOR using ultra high-performance liquid chromatography and mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2017; 1072:244-251. [PMID: 29195143 DOI: 10.1016/j.jchromb.2017.11.027] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 11/14/2017] [Accepted: 11/22/2017] [Indexed: 02/06/2023]
Abstract
PP242 is a second generation novel selective ATP-competitive inhibitor of mTOR that displayed promising anti-cancer activity over several cancer types by inhibiting both the complexes of mTOR (mTORC1 and mTORC2). The purpose of this study is to identify the possible metabolites and to evaluate the pharmacokinetic profile of PP242 after a single oral administration to Sprague-Dawley (SD) rats. Two metabolites, including one phase I and one phase II, were identified by in vitro and in vivo studies using rat liver microsomes (RLMs) as well as rat plasma, urine and feces, respectively, through ultra high-performance liquid chromatography-linear ion trap quadrupole-orbitrap-mass spectrometry (UHPLC-LTQ-Orbitrap-MS). The major biotransformation pathways of PP242 were hydroxylation and glucuronide conjugation. Additionally, a simple and rapid quantification method was developed and validated. The method recovery was within 79.7-84.6%, whereas the matrix effect was 78.1-96.0% in all three quality control (QC) concentrations (low, medium and high) including the LLOQ. Other parameters showed acceptable results according to the US food and drug administration (FDA) guidelines for bioanalytical method validation. Afterwards, pharmacokinetic parameters were evaluated in rat plasma by successfully applying the validated method using liquid chromatography-tandem mass spectrometry (LC-MS/MS). After a single oral administration at a dose of 5mg/kg, the maximum plasma concentration (Cmax) of PP242 was 0.17±0.08μg/mL, while the elimination was moderately fast (T1/2: 172.18±45.54min). All of the obtained information on the metabolite identification and pharmacokinetic parameter elucidation could facilitate the further development of PP242.
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Affiliation(s)
- Md Mamunur Rashid
- Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology (UST), Seoul 02792, Republic of Korea
| | - Hyunbeom Lee
- Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
| | - Byung Hwa Jung
- Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology (UST), Seoul 02792, Republic of Korea.
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Li S, Hsu CW, Sakamuru S, Zou C, Huang R, Xia M. Identification of Angiogenesis Inhibitors Using a Co-culture Cell Model in a High-Content and High-Throughput Screening Platform. SLAS Technol 2017; 23:217-225. [PMID: 28922619 PMCID: PMC6032403 DOI: 10.1177/2472630317729792] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Angiogenesis is an important hallmark of cancer, contributing to tumor formation
and metastasis. In vitro angiogenesis models for analyzing tube formation serve
as useful tools to study these processes. However, current in vitro co-culture
models using primary cells have limitations in usefulness and consistency.
Therefore, in the present study, an in vitro co-culture assay system was
optimized in a 1536-well format for high-throughput screening using human
telomerase reverse transcriptase (hTERT)–immortalized mesenchymal stem cells and
aortic endothelial cells. The National Center for Advancing Translational
Sciences (NCATS) Pharmaceutical Collection (NPC) library containing 2816 drugs
was evaluated using the in vitro co-culture assay. From the screen, 35 potent
inhibitors (IC50 ≤1 µM) were identified, followed by 15 weaker
inhibitors (IC50 1–50 µM). Moreover, many known angiogenesis
inhibitors were identified, such as topotecan, docetaxel, and bortezomib.
Several potential novel angiogenesis inhibitors were also identified from this
study, including thimerosal and podofilox. Among the inhibitors, some compounds
were proved to be involved in the hypoxia-inducible factor-1α (HIF-1α) and the
nuclear factor-kappa B (NF-κB) pathways. The co-culture model developed by using
hTERT-immortalized cell lines described in this report provides a consistent and
robust in vitro system for antiangiogenic drug screening.
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Affiliation(s)
- Shuaizhang Li
- 1 Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA
| | - Chia-Wen Hsu
- 1 Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA
| | - Srilatha Sakamuru
- 1 Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA
| | - Chaozhong Zou
- 2 American Type Culture Collection, Gaithersburg, MD, USA
| | - Ruili Huang
- 1 Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA
| | - Menghang Xia
- 1 Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA
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Zhang C, Yan J, Xiao Y, Shen Y, Wang J, Ge W, Chen Y. Inhibition of Autophagic Degradation Process Contributes to Claudin-2 Expression Increase and Epithelial Tight Junction Dysfunction in TNF-α Treated Cell Monolayers. Int J Mol Sci 2017; 18:157. [PMID: 28106723 PMCID: PMC5297790 DOI: 10.3390/ijms18010157] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 01/01/2017] [Accepted: 01/10/2017] [Indexed: 02/06/2023] Open
Abstract
Tight junction dysfunction plays a vital role in some chronic inflammatory diseases. Pro-inflammatory cytokines, especially tumor necrosis factor alpha (TNF-α), act as important factors in intestinal epithelial tight junction dysfunction during inflammatory conditions. Autophagy has also been shown to be crucial in tight junction function and claudin-2 expression, but whether autophagy has an effect on the change of claudin-2 expression and tight junction function induced by TNF-α is still unknown. To answer this question, we examined the expression of claudin-2 protein, transepithelial electrical resistance (TER), and permeability of cell monolayers, autophagy flux change, and lysosomal pH after TNF-α with or without PP242 treatment. Our study showed that claudin-2 expression, intestinal permeability, microtubule-associated protein 1 light chain 3B II (LC3B-II) and sequestosome 1 (P62) expression largely increased while TER values decreased in TNF-α treated cell monolayers. Further research using 3-methyladenine (3-MA), bafilomycin A1, and ad-mCherry-GFP-LC3B adenovirus demonstrated that LC3B-II increase induced by TNF-α was attributed to the inhibition of autophagic degradation. Moreover, both qualitative and quantitative method confirmed the increase of lysosomal pH, and mammalian target of rapamycin (mTOR) inhibitor PP242 treatment relieved this elevation. Moreover, PP242 treatment also alleviated the change of autophagy flux, TER, and claudin-2 expression induced by TNF-α. Therefore, we conclude that increase of claudin-2 levels and intestinal epithelial tight junction dysfunction are partly caused by the inhibition of autophagic degradation in TNF-α treated cell monolayers.
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Affiliation(s)
- Cong Zhang
- Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
| | - Junkai Yan
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai 200092, China.
| | - Yongtao Xiao
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai 200092, China.
| | - Yujie Shen
- Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
| | - Jiazheng Wang
- Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
| | - Wensong Ge
- Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
| | - Yingwei Chen
- Department of Gastroenterology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai 200092, China.
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Karras JR, Schrock MS, Batar B, Zhang J, La Perle K, Druck T, Huebner K. Fhit loss-associated initiation and progression of neoplasia in vitro. Cancer Sci 2016; 107:1590-1598. [PMID: 27513973 PMCID: PMC5132276 DOI: 10.1111/cas.13032] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 08/05/2016] [Accepted: 08/09/2016] [Indexed: 12/28/2022] Open
Abstract
The FHIT gene, encompassing an active common fragile site, FRA3B, is frequently silenced in preneoplasia and cancer, through gene rearrangement or methylation of regulatory sequences. Silencing of Fhit protein expression causes thymidine kinase 1 downregulation, resulting in dNTP imbalance, and spontaneous replication stress that leads to chromosomal aberrations, allele copy number variations, insertions/deletions, and single-base substitutions. Thus, Fhit, which is reduced in expression in the majority of human cancers, is a genome "caretaker" whose loss initiates genome instability in preneoplastic lesions. To follow the early genetic alterations and functional changes induced by Fhit loss that may recapitulate the neoplastic process in vitro, we established epithelial cell lines from kidney tissues of Fhit-/- and +/+ mouse pups early after weaning, and subjected cell cultures to nutritional and carcinogen stress, which +/+ cells did not survive. Through transcriptome profiling and protein expression analysis, we observed changes in the Trp53/p21 and survivin apoptotic pathways in -/- cells, and in expression of proteins involved in epithelial-mesenchymal transition. Some Fhit-deficient cell lines showed anchorage-independent colony formation and increased invasive capacity in vitro. Furthermore, cells of stressed Fhit-/- cell lines formed s.c. and metastatic tumors in nude mice. Collectively, we show that Fhit loss and subsequent thymidine kinase 1 inactivation, combined with selective pressures, leads to neoplasia-associated alterations in genes and gene expression patterns in vitro and in vivo.
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Affiliation(s)
- Jenna R. Karras
- Department of Cancer Biology and GeneticsOhio State University Wexner Medical CenterColumbusOhioUSA
| | - Morgan S. Schrock
- Department of Cancer Biology and GeneticsOhio State University Wexner Medical CenterColumbusOhioUSA
| | - Bahadir Batar
- Department of Cancer Biology and GeneticsOhio State University Wexner Medical CenterColumbusOhioUSA
| | - Jie Zhang
- Department of Biomedical InformaticsOhio State University Wexner Medical CenterColumbusOhioUSA
| | - Krista La Perle
- Department of Veterinary BiosciencesCollege of Veterinary MedicineOhio State UniversityColumbusOhioUSA
| | - Teresa Druck
- Department of Cancer Biology and GeneticsOhio State University Wexner Medical CenterColumbusOhioUSA
| | - Kay Huebner
- Department of Cancer Biology and GeneticsOhio State University Wexner Medical CenterColumbusOhioUSA
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36
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Hong Y, Chen W, Du X, Ning H, Chen H, Shi R, Lin S, Xu R, Zhu J, Wu S, Zhou H. Upregulation of sex-determining region Y-box 9 (SOX9) promotes cell proliferation and tumorigenicity in esophageal squamous cell carcinoma. Oncotarget 2016; 6:31241-54. [PMID: 26384302 PMCID: PMC4741601 DOI: 10.18632/oncotarget.5160] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 08/24/2015] [Indexed: 02/06/2023] Open
Abstract
Sex-determining region Y-box 9 (SOX9), a vital transcription factor, play important roles in numerous biological and pathological processes. However, the clinical significance and biological role of SOX9 expression has not been characterized in human esophageal squamous cell cancer (ESCC). Herein, we found that SOX9 was markedly upregulated, at both mRNA and protein level, in ESCC cell lines and ESCC tissues and that SOX9 expression was significantly correlated with tumor clinical stage, T classification, N classification, M classification, pathological differentiation, and shorter overall survival. The proliferation and tumorigenicity of ESCC cells were dramatically induced by SOX9 overexpression but were inhibited by SOX9 knockdown both in vitro and in vivo. Moreover, we demonstrated that upregulation of SOX9 increased the expression of phosphorylated Akt, the cyclin-dependent kinase (CDK) regulator cyclin D1, phosphorylated forkhead box O (FOXO)1, and phosphorylated FOXO3, but SOX9 downregulation decreased their expression, whereas the levels of the CDK inhibitors p21Cip1 and p27Kip1 were attenuated in SOX9-transduced cells. Taken together, our results suggest that SOX9 plays an important role in promoting the proliferation and tumorigenesis of ESCC and may represent a novel prognostic marker for the disease.
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Affiliation(s)
- Yingcai Hong
- Department of Thoracic Surgery, Shenzhen People's Hospital, the Second Clinical Medical College of Jinan University, Shenzhen 510000, China
| | - Wen Chen
- Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, China
| | - Xiaojun Du
- Department of Thoracic Surgery, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China
| | - Huiwen Ning
- Department of Anorectal Surgery, Shenzhen Second People's Hospital, Shenzhen 518035, China
| | - Huaisheng Chen
- Intensive Care Unit, Shenzhen People's Hospital, the Second Clinical Medical College of Jinan University, Shenzhen 510000, China
| | - Ruiqing Shi
- Department of Thoracic Surgery, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China
| | - Shaolin Lin
- Department of Thoracic Surgery, Shenzhen People's Hospital, the Second Clinical Medical College of Jinan University, Shenzhen 510000, China
| | - Rongyu Xu
- Department of Thoracic Surgery, Quanzhou First Hospital, the Affiliated Hospital of Fujian Medical University, Quanzhou 362000, China
| | - Jinrong Zhu
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Shu Wu
- State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Haiyu Zhou
- Department of Thoracic Surgery, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China
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37
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Weber H, Leal P, Stein S, Kunkel H, García P, Bizama C, Espinoza JA, Riquelme I, Nervi B, Araya JC, Grez M, Roa JC. Rapamycin and WYE-354 suppress human gallbladder cancer xenografts in mice. Oncotarget 2016; 6:31877-88. [PMID: 26397134 PMCID: PMC4741647 DOI: 10.18632/oncotarget.5047] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 09/01/2015] [Indexed: 01/17/2023] Open
Abstract
Gallbladder cancer (GBC) is a highly malignant tumor characterized by a poor response to chemotherapy and radiotherapy. We evaluated the in vitro and in vivo antitumor efficacy of mTOR inhibitors, rapamycin and WYE-354. In vitro assays showed WYE-354 significantly reduced cell viability, migration and invasion and phospho-P70S6K expression in GBC cells. Mice harboring subcutaneous gallbladder tumors, treated with WYE-354 or rapamycin, exhibited a significant reduction in tumor mass. A short-term treatment with a higher dose of WYE-354 decreased the tumor size by 68.6% and 52.4%, in mice harboring G-415 or TGBC-2TKB tumors, respectively, compared to the control group. By contrast, treatment with a prolonged-low-dose regime of rapamycin almost abrogated tumor growth, exhibiting 92.7% and 97.1% reduction in tumor size, respectively, compared to control mice. These results were accompanied by a greater decrease in the phosphorylation status of P70S6K and a lower cell proliferation Ki67 index, compared to WYE-354 treated mice, suggesting a more effective mTOR pathway inhibition. These findings provide a proof of concept for the use of rapamycin or WYE-354 as potentially good candidates to be studied in clinical trials in GBC patients.
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Affiliation(s)
- Helga Weber
- Department of Pathology, Center of Genetic and Immunological Studies (CEGIN) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Pamela Leal
- Department of Pathology, Center of Genetic and Immunological Studies (CEGIN) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Stefan Stein
- Gene Therapy Unit, Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany
| | - Hana Kunkel
- Gene Therapy Unit, Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany
| | - Patricia García
- Department of Pathology, UC-Center for Investigational Oncology (CITO), Advanced Center for Chronic Diseases (ACCDiS), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Bizama
- Department of Pathology, UC-Center for Investigational Oncology (CITO), Advanced Center for Chronic Diseases (ACCDiS), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Jaime A Espinoza
- Department of Pathology, UC-Center for Investigational Oncology (CITO), Advanced Center for Chronic Diseases (ACCDiS), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ismael Riquelme
- Department of Pathology, Center of Genetic and Immunological Studies (CEGIN) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Bruno Nervi
- Department of Hematology Oncology, UC-Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan C Araya
- Department of Pathology, Center of Genetic and Immunological Studies (CEGIN) and Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - Manuel Grez
- Gene Therapy Unit, Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany
| | - Juan C Roa
- Department of Pathology, UC-Center for Investigational Oncology (CITO), Advanced Center for Chronic Diseases (ACCDiS), School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
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38
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Ke B, Tian M, Li J, Liu B, He G. Targeting Programmed Cell Death Using Small-Molecule Compounds to Improve Potential Cancer Therapy. Med Res Rev 2016; 36:983-1035. [PMID: 27357603 DOI: 10.1002/med.21398] [Citation(s) in RCA: 134] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 05/04/2016] [Accepted: 05/28/2016] [Indexed: 02/05/2023]
Affiliation(s)
- Bowen Ke
- Department of Anesthesiology, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital, Sichuan University; Chengdu 610041 China
| | - Mao Tian
- Department of Anesthesiology, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital, Sichuan University; Chengdu 610041 China
| | - Jingjing Li
- Department of Anesthesiology, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital, Sichuan University; Chengdu 610041 China
| | - Bo Liu
- Department of Anesthesiology, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital, Sichuan University; Chengdu 610041 China
| | - Gu He
- Department of Anesthesiology, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital, Sichuan University; Chengdu 610041 China
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39
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Tas SW, Maracle CX, Balogh E, Szekanecz Z. Targeting of proangiogenic signalling pathways in chronic inflammation. Nat Rev Rheumatol 2015; 12:111-22. [PMID: 26633288 DOI: 10.1038/nrrheum.2015.164] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Angiogenesis is de novo capillary outgrowth from pre-existing blood vessels. This process not only is crucial for normal development, but also has an important role in supplying oxygen and nutrients to inflamed tissues, as well as in facilitating the migration of inflammatory cells to the synovium in rheumatoid arthritis, spondyloarthritis and other systemic autoimmune diseases. Neovascularization is dependent on the balance of proangiogenic and antiangiogenic mediators, including growth factors, cytokines, chemokines, cell adhesion molecules and matrix metalloproteinases. This Review describes the various intracellular signalling pathways that govern these angiogenic processes and discusses potential approaches to interfere with pathological angiogenesis, and thereby ameliorate inflammatory disease, by targeting these pathways.
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Affiliation(s)
- Sander W Tas
- Amsterdam Rheumatology &Immunology Centre, Department of Experimental Immunology, Academic Medical Centre and University of Amsterdam, EULAR &FOCIS (Federation of Clinical Immunology Societies) Centre of Excellence, Meibergdreef 9, F4-105, 1105 AZ Amsterdam, Netherlands
| | - Chrissta X Maracle
- Amsterdam Rheumatology &Immunology Centre, Department of Experimental Immunology, Academic Medical Centre and University of Amsterdam, EULAR &FOCIS (Federation of Clinical Immunology Societies) Centre of Excellence, Meibergdreef 9, F4-105, 1105 AZ Amsterdam, Netherlands
| | - Emese Balogh
- Department of Rheumatology, Institute of Medicine, University of Debrecen, Faculty of Medicine, Nagyerdei Str. 98, Debrecen 4032, Hungary
| | - Zoltán Szekanecz
- Department of Rheumatology, Institute of Medicine, University of Debrecen, Faculty of Medicine, Nagyerdei Str. 98, Debrecen 4032, Hungary
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40
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Singh SS, Yap WN, Arfuso F, Kar S, Wang C, Cai W, Dharmarajan AM, Sethi G, Kumar AP. Targeting the PI3K/Akt signaling pathway in gastric carcinoma: A reality for personalized medicine? World J Gastroenterol 2015; 21:12261-12273. [PMID: 26604635 PMCID: PMC4649111 DOI: 10.3748/wjg.v21.i43.12261] [Citation(s) in RCA: 137] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 08/11/2015] [Accepted: 10/26/2015] [Indexed: 02/06/2023] Open
Abstract
Frequent activation of phosphatidylinositol-3 kinases (PI3K)/Akt/mTOR signaling pathway in gastric cancer (GC) is gaining immense popularity with identification of mutations and/or amplifications of PIK3CA gene or loss of function of PTEN, a tumor suppressor protein, to name a few; both playing a crucial role in regulating this pathway. These aberrations result in dysregulation of this pathway eventually leading to gastric oncogenesis, hence, there is a need for targeted therapy for more effective anticancer treatment. Several inhibitors are currently in either preclinical or clinical stages for treatment of solid tumors like GC. With so many inhibitors under development, further studies on predictive biomarkers are needed to measure the specificity of any therapeutic intervention. Herein, we review the common dysregulation of PI3K/Akt/mTOR pathway in GC and the various types of single or dual pathway inhibitors under development that might have a superior role in GC treatment. We also summarize the recent developments in identification of predictive biomarkers and propose use of predictive biomarkers to facilitate more personalized cancer therapy with effective PI3K/Akt/mTOR pathway inhibition.
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41
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Zhang Z, Zhang G, Kong C, Gong D. PP242 suppresses bladder cancer cell proliferation and migration through deactivating the mammalian target of rapamycin complex 2/AKT1 signaling pathway. Mol Med Rep 2015; 13:333-8. [PMID: 26548560 DOI: 10.3892/mmr.2015.4528] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2015] [Accepted: 10/06/2015] [Indexed: 11/06/2022] Open
Abstract
While most cancer types are resistant to mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin, recent studies have identified mTORC2 as an important prospective therapeutic target for cancer. The present study assessed the effects of mTORC2 inhibitor PP242 on the proliferation and migration of bladder cancer cells by using Cell Counting Kit‑8, 5‑ethynyl‑2'‑deoxyuridine incorporation, wound healing and Transwell assays. Furthermore, the phosphorylation status of downstream signaling proteins of mTORC1 and mTORC2 was assessed using western blot analysis. The results demonstrated that PP242 concentration‑dependently inhibited the proliferation of bladder cancer cells. Simultaneously, the migration ability of bladder cancer cells was suppressed by PP242. In addition, PP242 markedly restrained the phosphorylation of AKT1 and mTORC2, while the phosphorylation status of S6K1 and mTORC1 was not affected. These results suggested that PP242 exerts potent inhibitory effects on bladder cancer cells by modulating the activity of the mTORC2/AKT1 pathway.
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Affiliation(s)
- Zhe Zhang
- Department of Urology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Guojun Zhang
- Department of Hematology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110022, P.R. China
| | - Chuize Kong
- Department of Urology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Daxin Gong
- Department of Urology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
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Zhang XY, Kuang JL, Yan CS, Tu XY, Zhao JH, Cheng XS, Ye XQ. NRSN2 promotes non-small cell lung cancer cell growth through PI3K/Akt/mTOR pathway. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:2574-81. [PMID: 26045763 PMCID: PMC4440072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 02/20/2015] [Indexed: 06/04/2023]
Abstract
Neurensin-2 (NRSN2), a small neural membrane protein which localized in small vesicles in neural cells. Recent report suggested that Neurensin-2 might play a suppressive role in tumor. While the biological functions and molecular mechanisms in cancer progression remain unknown. We retrieved Oncomine Database and found that NRSN2 is commonly highly expressed in non-small cell lung cancer (NSCLC). We examined the levels of NRSN2 in 18 pairs of NSCLC and adjacent tissues and found that NRSN2 was overexpressed in malignant tissues. Both loss and gain of function experiments in NSCLC cell lines suggest that NRSN2 promotes cell growth, but no effects in cell invasion. Further investigation show that NRSN2 could affect phosphatidylinositol 3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling. Taken together, our findings suggest that NRSN2 promotes non-small cell lung cancer cell growth through PI3K/Akt/mTOR pathway.
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Affiliation(s)
- Xin-Yi Zhang
- Department of Respiratory Diseases, The Second Affiliated Hospital of Nanchang UniversityNanchang 330006, China
| | - Jiu-Long Kuang
- Department of Respiratory Diseases, The Second Affiliated Hospital of Nanchang UniversityNanchang 330006, China
| | - Chun-Song Yan
- Department of Respiratory Diseases, The Second Affiliated Hospital of Nanchang UniversityNanchang 330006, China
| | - Xiao-Yun Tu
- Department of Respiratory Diseases, The Second Affiliated Hospital of Nanchang UniversityNanchang 330006, China
| | - Ji-Hua Zhao
- Department of Respiratory Diseases, The Second Affiliated Hospital of Nanchang UniversityNanchang 330006, China
| | - Xiao-Shu Cheng
- Department of Cardiology, The Second Affiliated Hospital of Nanchang UniversityNanchang 330006, China
| | - Xiao-Qun Ye
- Department of Respiratory Diseases, The Second Affiliated Hospital of Nanchang UniversityNanchang 330006, China
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Targeting of mTORC2 may have advantages over selective targeting of mTORC1 in the treatment of malignant pheochromocytoma. Tumour Biol 2015; 36:5273-81. [DOI: 10.1007/s13277-015-3187-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2014] [Accepted: 01/30/2015] [Indexed: 10/24/2022] Open
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Significantly inhibitory effects of low molecular weight heparin (Fraxiparine) on the motility of lung cancer cells and its related mechanism. Tumour Biol 2015; 36:4689-97. [PMID: 25619477 DOI: 10.1007/s13277-015-3117-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 01/14/2015] [Indexed: 02/05/2023] Open
Abstract
Low molecular weight heparin (LMWH) improving the cancer survival has been attracting attention for many years. Our previous study found that LMWH (Fraxiparine) strongly downregulated the invasive, migratory, and adhesive ability of human lung adenocarcinoma A549 cells. Here, we aimed to further identify the antitumor effects and possible mechanisms of Fraxiparine on A549 cells and human highly metastatic lung cancer 95D cells. The ability of cell invasion, migration, and adhesion were measured by Transwell, Millicell, and MTT assays. FITC-labeled phalloidin was used to detect F-actin bundles in cells. Chemotactic migration was analyzed in a modified Transwell assay. Measurement of protein expression and phosphorylation activity of PI3K, Akt, and mTOR was performed with Western blot. Our studies found that Fraxiparine significantly inhibited the invasive, migratory, and adhesive characteristics of A549 and 95D cells after 24 h incubation and showed a dose-dependent manner. Fraxiparine influenced the actin cytoskeleton rearrangement of A549 and 95D cells by preventing F-actin polymerization. Moreover, Fraxiparine could significantly inhibit CXCL12-mediated chemotactic migration of A549 and 95D cells in a concentration-dependent manner. Furthermore, Fraxiparine might destroy the interaction between CXCL12-CXCR4 axis, then suppress the PI3K-Akt-mTOR signaling pathway in lung cancer cells. For the first time, our data indicated that Fraxiparine could significantly inhibit the motility of lung cancer cells by restraining the actin cytoskeleton reorganization, and its related mechanism might be through inhibiting PI3K-Akt-mTOR signaling pathway mediated by CXCL12-CXCR4 axis. Therefore, Fraxiparine would be a potential drug for lung cancer metastasis therapy.
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Genomic assays for Epstein-Barr virus-positive gastric adenocarcinoma. Exp Mol Med 2015; 47:e134. [PMID: 25613731 PMCID: PMC4314585 DOI: 10.1038/emm.2014.93] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Accepted: 10/06/2014] [Indexed: 12/13/2022] Open
Abstract
A small set of gastric adenocarcinomas (9%) harbor Epstein–Barr virus (EBV) DNA within malignant cells, and the virus is not an innocent bystander but rather is intimately linked to pathogenesis and tumor maintenance. Evidence comes from unique genomic features of host DNA, mRNA, microRNA and CpG methylation profiles as revealed by recent comprehensive genomic analysis by The Cancer Genome Atlas Network. Their data show that gastric cancer is not one disease but rather comprises four major classes: EBV-positive, microsatellite instability (MSI), genomically stable and chromosome instability. The EBV-positive class has even more marked CpG methylation than does the MSI class, and viral cancers have a unique pattern of methylation linked to the downregulation of CDKN2A (p16) but not MLH1. EBV-positive cancers often have mutated PIK3CA and ARID1A and an amplified 9p24.1 locus linked to overexpression of JAK2, CD274 (PD-L1) and PDCD1LG2 (PD-L2). Multiple noncoding viral RNAs are highly expressed. Patients who fail standard therapy may qualify for enrollment in clinical trials targeting cancer-related human gene pathways or promoting destruction of infected cells through lytic induction of EBV genes. Genomic tests such as the GastroGenus Gastric Cancer Classifier are available to identify actionable variants in formalin-fixed cancer tissue of affected patients.
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