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Klein-Goldberg A, Voloshin T, Zemer Tov E, Paz R, Somri-Gannam L, Volodin A, Koren L, Lifshitz L, Meir A, Shabtay-Orbach A, Blatt R, Cahal S, Tempel-Brami C, Wainer-Katsir K, Kan T, Koltun B, Brant B, Barsheshet Y, Haber A, Giladi M, Weinberg U, Palti Y. Role of the PI3K/AKT signaling pathway in the cellular response to Tumor Treating Fields (TTFields). Cell Death Dis 2025; 16:210. [PMID: 40148314 PMCID: PMC11950169 DOI: 10.1038/s41419-025-07546-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 02/18/2025] [Accepted: 03/17/2025] [Indexed: 03/29/2025]
Abstract
Tumor Treating Fields (TTFields) are electric fields that induce cancer cell death. Genomic analysis of glioblastoma tumors resected from TTFields-treated patients suggested a potential link between a reduced or absent response to TTFields and activating mutations in the phosphatidylinositol 3-kinase (PI3K) p110α subunit (PIK3CA). Our study aimed to investigate the role of the PI3K/AKT pathway in the response to TTFields. We tested changes in signaling pathways in control versus TTFields-treated U-87 MG glioblastoma, A2780 ovarian carcinoma, and H1299 non-small cell lung cancer (NSCLC) cells using the Luminex multiplex assay, validated by western blot analysis and inhibition assays. We also performed in vivo validation using immunohistochemistry on tumor sections from animals bearing orthotopic N1-S1 hepatocellular, MOSE-L ovarian, or LL/2 lung tumors that were treated with TTFields or sham. Finally, we examined the efficacy of concomitant treatment with TTFields and PI3K inhibitors in cell lines and mouse models. Our findings elucidate the mechanisms driving PI3K/AKT activation following TTFields treatment, revealing that the AKT signaling amplitude increases over time and is influenced by cell-surface and cell-cell interactions. Specifically, focal adhesion kinase (FAK) and N-cadherin were found to promote AKT phosphorylation, activating cell survival pathways. Furthermore, our investigation revealed that pharmacological inhibition of PI3K sensitized cancer cells to TTFields, both in vitro and in vivo. Our research suggests that the PI3K/AKT pathway is involved in cancer cell response to TTFields, and that inhibition of this pathway may serve as a potential therapeutic target for sensitizing cancer cells to TTFields.
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Jin C, Gao X, Ni J, Zhang B, Wang Z. MiR-592 Attenuates Tamoxifen Resistance in Breast Cancer Through PIK3CA-Mediated PI3K/AKT/mTOR Signaling Pathway. Appl Biochem Biotechnol 2025; 197:2051-2065. [PMID: 39661080 DOI: 10.1007/s12010-024-05123-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/19/2024] [Indexed: 12/12/2024]
Abstract
Tamoxifen (TAM) is vital in breast cancer (BC) treatment, yet its resistance significantly impairs its efficacy. While miR-592 is known for its suppressive role in BC, its effect on chemotherapy resistance remains unclear. In this study, we observed a significant reduction in miR-592 levels in TAM-resistant BC tissues and cell lines. Low miR-592 expression was significantly associated with advanced TNM stage, lymph node metastasis, and poorer patient survival. Dual-luciferase assay confirmed miR-592 binding to the predicted gene PIK3CA. Increasing miR-592 levels decreased the IC50 of TAM, inhibited cell viability, migration, and invasion, and enhanced apoptosis in vitro, which was mimicked by PIK3CA knockdown and reversed by PIK3CA overexpression. Moreover, miR-592 upregulation suppressed tumor growth and improved TAM responsiveness in vivo. Molecularly, both si-PIK3CA and miR-592 mimics decreased the expression ratios of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR, while increasing cleaved caspase-3 and E-cadherin expression in MCF-7/TAM cells. PIK3CA overexpression partially reversed these reductions. In conclusion, our study demonstrates that miR-592 attenuates TAM resistance by inhibiting the PIK3CA-driven PI3K/AKT/mTOR signaling pathway, representing a promising strategy to address chemoresistance in BC.
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Affiliation(s)
- Conghui Jin
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, P.R. China
- Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Nantong, 226361, Jiangsu, P.R. China
| | - Xiangxiang Gao
- Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Nantong, 226361, Jiangsu, P.R. China
| | - Jingyi Ni
- Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Nantong, 226361, Jiangsu, P.R. China
| | - Baochun Zhang
- Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Nantong, 226361, Jiangsu, P.R. China
| | - Zhenxin Wang
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, P.R. China.
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Saadh MJ, Ehymayed HM, Alazzawi TS, Fahdil AA, Athab ZH, Yarmukhamedov B, Al-Anbari HHA, Shallal MM, Alsaikhan F, Farhood B. Role of circRNAs in regulating cell death in cancer: a comprehensive review. Cell Biochem Biophys 2025; 83:109-133. [PMID: 39243349 DOI: 10.1007/s12013-024-01492-6] [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] [Accepted: 08/21/2024] [Indexed: 09/09/2024]
Abstract
Despite multiple diagnostic and therapeutic advances, including surgery, radiation therapy, and chemotherapy, cancer preserved its spot as a global health concern. Prompt cancer diagnosis, treatment, and prognosis depend on the discovery of new biomarkers and therapeutic strategies. Circular RNAs (circRNAs) are considered as a stable, conserved, abundant, and varied group of RNA molecules that perform multiple roles such as gene regulation. There is evidence that circRNAs interact with RNA-binding proteins, especially capturing miRNAs. An extensive amount of research has presented the substantial contribution of circRNAs in various types of cancer. To fully understand the linkage between circRNAs and cancer growth as a consequence of various cell death processes, including autophagy, ferroptosis, and apoptosis, more research is necessary. The expression of circRNAs could be controlled to limit the occurrence and growth of cancer, providing a more encouraging method of cancer treatment. Consequently, it is critical to understand how circRNAs affect various forms of cancer cell death and evaluate whether circRNAs could be used as targets to induce tumor death and increase the efficacy of chemotherapy. The current study aims to review and comprehend the effects that circular RNAs exert on cell apoptosis, autophagy, and ferroptosis in cancer to investigate potential cancer treatment targets.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | | | - Tuqa S Alazzawi
- College of dentist, National University of Science and Technology, Dhi Qar, Iraq
| | - Ali A Fahdil
- Medical technical college, Al-Farahidi University, Baghdad, Iraq
| | - Zainab H Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Bekhzod Yarmukhamedov
- Department of Surgical Dentistry and Dental Implantology, Tashkent State Dental Institute, Tashkent, Uzbekistan
- Department of Scientific affairs, Samarkand State Medical University, Samarkand, Uzbekistan
| | | | | | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia.
- School of Pharmacy, Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia.
| | - Bagher Farhood
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Vaghari-Tabari M, Qujeq D, Hashemzadeh MS. Long noncoding RNAs as potential targets for overcoming chemoresistance in upper gastrointestinal cancers. Biomed Pharmacother 2024; 179:117368. [PMID: 39214010 DOI: 10.1016/j.biopha.2024.117368] [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: 05/27/2024] [Revised: 08/16/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024] Open
Abstract
In the last decade, researchers have paid much attention to the role of noncoding RNA molecules in human diseases. Among the most important of these molecules are LncRNAs, which are RNA molecules with a length of more than 200 nucleotides. LncRNAs can regulate gene expression through various mechanisms, such as binding to DNA sequences and interacting with miRNAs. Studies have shown that LncRNAs may be valuable therapeutic targets in treating various cancers, including upper-gastrointestinal cancers. Upper gastrointestinal cancers, mainly referring to esophageal and gastric cancers, are among the deadliest gastrointestinal cancers. Despite notable advances, traditional chemotherapy remains a common strategy for treating these cancers. However, chemoresistance poses a significant obstacle to the effective treatment of upper gastrointestinal cancers, resulting in a low survival rate. Chemoresistance arises from various events, such as the enhancement of efflux and detoxification of chemotherapy agents, reduction of drug uptake, alteration of drug targeting, reduction of prodrug activation, strengthening of EMT and stemness, and the attenuation of apoptosis in cancerous cells. Tumor microenvironment also plays an important role in chemoresistance. Interestingly, a series of studies have revealed that LncRNAs can influence important mechanisms associated with some of the aforementioned events and may serve as promising targets for mitigating chemoresistance in upper gastrointestinal cancers. In this review paper, following a concise overview of chemoresistance mechanisms in upper gastrointestinal cancers, we will review the most intriguing findings of these investigations in detail.
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Affiliation(s)
- Mostafa Vaghari-Tabari
- Department of Paramedicine, Amol School of Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
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Wei J, Ji K, Zhang Y, Zhang J, Wu X, Ji X, Zhou K, Yang X, Lu H, Wang A, Bu Z. Exploration of molecular markers related to chemotherapy efficacy of hepatoid adenocarcinoma of the stomach. Cell Oncol (Dordr) 2024; 47:677-693. [PMID: 37943484 DOI: 10.1007/s13402-023-00892-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/08/2023] [Indexed: 11/10/2023] Open
Abstract
PURPOSE Preoperative neoadjuvant chemotherapy may not improve the prognosis of patients with hepatoid adenocarcinoma of the stomach (HAS), a rare pathological type of gastric cancer. Thus, the study aimed at the genomic and transcriptomic impacts of preoperative chemotherapy on HAS. METHODS Patients with HAS who underwent surgical resection at Peking University Cancer Hospital were retrospectively included in this study. Whole exome sequencing and transcriptome sequencing were performed on pre-chemotherapy, non-chemotherapy and post-chemotherapy samples. We then compared the alterations in molecular markers between the post-chemotherapy and non-chemotherapy groups, and between the chemotherapy-effective and chemotherapy-ineffective groups, respectively. RESULTS A total of 79 tumor samples from 72 patients were collected. Compared to the non-chemotherapy group, the mutation frequencies of several genes were changed after chemotherapy, including TP53. In addition, there was a significant increase in the frequency of frameshift mutations and cytosine transversion to adenine (C > A), appearance of COSMIC signature 6 and 14, and a reduced gene copy number amplification. Interestingly, the same phenomenon was observed in chemotherapy-ineffective patients. In addition, many HAS patients had ERBB2, FGFR2, MET and HGF gene amplification. Moreover, the expression of immune-related genes, especially those related to lymphocyte activation, was down-regulated after chemotherapy. CONCLUSION Chemotherapy is closely associated with changes in the molecular characteristics of HAS. After chemotherapy, at genomic and transcriptome level, many features were altered. These changes may be molecular markers of poor chemotherapeutic efficacy and play an important role in chemoresistance in HAS. In addition, ERBB2, FGFR2, MET and HGF gene amplification may be potential therapeutic targets for HAS.
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Affiliation(s)
- Jingtao Wei
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Ke Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Yue Zhang
- Beijing Key Laboratory of Preclinical Research and Evaluation for Cardiovascular Implant Materials, Animal Experimental Centre, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
- The Cardiomyopathy Research Group at Fuwai Hospital, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Beijing, 100037, China
| | - Ji Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Xiaojiang Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Xin Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Kai Zhou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Xuesong Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Hongfeng Lu
- Berry Genomics Corporation, Beijing, 102206, China
| | - Anqiang Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China.
| | - Zhaode Bu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China.
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Abooshahab R, Al-Salami H, Dass CR. Synergy between PEDF and Doxorubicin in Breast Cancer Cells: Effects on Metastatic and Metabolic Pathways. Int J Mol Sci 2024; 25:2755. [PMID: 38474001 DOI: 10.3390/ijms25052755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 02/19/2024] [Accepted: 02/24/2024] [Indexed: 03/14/2024] Open
Abstract
Pigment epithelium-derived factor (PEDF), a serine protease inhibitor (Serpin) family member, shows promise in inhibiting tumour growth. In our study, we explored the effects of PEDF on the efficacy of the frontline chemotherapy agent doxorubicin (Dox) in BC cells. We found that Dox+PEDF treatment significantly reduced glucose uptake in MDA-MB-231 cells compared to the control (p = 0.0005), PEDF (p = 0.0137), and Dox (p = 0.0171) alone but paradoxically increased it in MCF-7 cells. Our findings further revealed that PEDF, Dox, and Dox+PEDF substantially hindered tumour cell migration from tumour spheroids, with Dox+PEDF showing the most significant impact (p < 0.0001). We also observed notable decreases in the expression of metastatic markers (uPAR, uPA, CXCR4, MT1-MMP, TNF-α) across all treatment groups (p < 0.0001) in both cell lines. When it comes to metabolic pathways, PEDF increased phosphorylated IRS-1 (p-IRS1) levels in MDA-MB-231 and MCF-7 (p < 0.0001), while Dox decreased it, and the combination led to an increase. In MDA-MB-231 cells, treatment with PEDF, Dox, and the combination led to a notable decrease in both phosphorylated AKT (p-AKT) and total AKT levels. In MCF-7, while PEDF, Dox, and their combination led to a reduction in p-AKT, total levels of AKT increased in the presence of Dox and Dox+PEDF. Combining PEDF with Dox enhances the targeting of metastatic and metabolic pathways in breast cancer cell lines. This synergy, marked by PEDF's increasing roles in cancer control, may pave the way for more effective cancer treatments.
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Affiliation(s)
- Raziyeh Abooshahab
- Curtin Medical School, Curtin University, Bentley 6102, Australia
- Curtin Health Innovation Research Institute, Bentley 6102, Australia
| | - Hani Al-Salami
- Curtin Medical School, Curtin University, Bentley 6102, Australia
- Biotechnology and Drug Development Research Laboratory, Curtin Health Innovation Research Institute, Bentley 6102, Australia
| | - Crispin R Dass
- Curtin Medical School, Curtin University, Bentley 6102, Australia
- Curtin Health Innovation Research Institute, Bentley 6102, Australia
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7
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Shah H, Hill TA, Lim J, Fairlie DP. Protease-activated receptor 2 attenuates doxorubicin-induced apoptosis in colon cancer cells. J Cell Commun Signal 2023:10.1007/s12079-023-00791-6. [PMID: 37991681 DOI: 10.1007/s12079-023-00791-6] [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: 01/31/2023] [Accepted: 11/02/2023] [Indexed: 11/23/2023] Open
Abstract
Drug resistance represents a major problem in cancer treatment. Doxorubicin (adriamycin) is an injectable DNA intercalating drug that halts cancer cell growth by inhibiting topoisomerase 2, but its long-term effectiveness is compromised by onset of resistance. This study demonstrates that expression of the PAR2 gene in human colon adenocarcinoma tissue samples was the highest among 32 different cancer types (n = 10,989), and higher in colon adenocarcinoma tissues (n = 331) than normal colon tissues (n = 308), revealing an association between PAR2 expression and human colon cancer. HT29 cells are a human colorectal adenocarcinoma cell line that is sensitive to the chemotherapeutic drug doxorubicin and also expresses PAR2. We find that PAR2 activation in HT29 cells, either by an endogenous protease agonist (trypsin) or an exogenous peptide agonist (2f-LIGRL-NH2), significantly reduces doxorubicin-induced cell death, reactive oxygen species production, caspase 3/7 activity and cleavage of caspase-8 and caspase-3. Moreover, PAR2-mediated MEK1/2-ERK1/2 pathway induced by 2f-LIGRL-NH2 leads to upregulated anti-apoptotic MCL-1 and Bcl-xL proteins that promote cellular survival. These findings suggest that activation of PAR2 compromises efficacy of doxorubicin in colon cancer. Further support for this conclusion came from experiments with human colon cancer HT29 cells, either with the PAR2 gene deleted or in the presence of a pharmacological antagonist of PAR2, which showed full restoration of all doxorubicin-mediated effects. Together, these findings reveal a strong link between PAR2 activation and signalling in human colon cancer cells and increased survival against doxorubicin-induced cell death. They support PAR2 antagonism as a possible new strategy for enhancing doxorubicin therapy.
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Affiliation(s)
- Himani Shah
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia
- Centre for Chemistry and Drug Discovery, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia
| | - Timothy A Hill
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia
- Centre for Chemistry and Drug Discovery, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia
| | - Junxian Lim
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia.
- Centre for Chemistry and Drug Discovery, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia.
| | - David P Fairlie
- Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia.
- Centre for Chemistry and Drug Discovery, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia.
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Al Khashali H, Darweesh B, Ray R, Haddad B, Wozniak C, Ranzenberger R, Goel S, Khalil J, Guthrie J, Heyl D, Evans HG. Regulation of Vascular Endothelial Growth Factor Signaling by Nicotine in a Manner Dependent on Acetylcholine-and/or β-Adrenergic-Receptors in Human Lung Cancer Cells. Cancers (Basel) 2023; 15:5500. [PMID: 38067204 PMCID: PMC10705358 DOI: 10.3390/cancers15235500] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 11/05/2023] [Accepted: 11/19/2023] [Indexed: 10/15/2024] Open
Abstract
Simple Summary Nicotine, a highly addictive component in cigarette smoke, facilitates tumorigenesis and the accelerated development of non-small cell lung cancer (NSCLC), which is known to account for ~80% of all lung cancer cases. This study sheds light on how the nicotine treatment of NSCLC cells regulates vascular endothelial growth factor (VEGF) signaling, known to be important in the progression of vascular disease and cancer, by acting through nicotinic acetylcholine receptors and by leading to the activation of β-adrenergic receptors through increased levels of the stress neurotransmitters, norepinephrine/noradrenaline, and epinephrine/adrenaline. Nicotine-induced activation of VEGF promoted the function of proteins involved in increased cell survival and suppressed the function of a crucial tumor suppressor, blocking cell death. This work expands our scientific knowledge of mechanisms employed by nicotine in regulating VEGF signaling in a manner dependent on the acetylcholine and/or β-adrenergic receptors, leading to lung cancer cell survival, and also provides significant insights into novel future therapeutic strategies to combat lung cancer. Abstract In addition to binding to nicotinic acetylcholine receptors (nAChRs), nicotine is known to regulate the β-adrenergic receptors (β-ARs) promoting oncogenic signaling. Using A549 (p53 wild-type) and H1299 (p53-null) lung cancer cells, we show that nicotine treatment led to: increased adrenaline/noradrenaline levels, an effect blocked by treatment with the α7nAChR inhibitor (α-BTX) but not by the β-blocker (propranolol) or the α4β2nAChR antagonist (DhβE); decreased GABA levels in A549 and H1299 cell media, an effect blocked by treatment with DhβE; increased VEGF levels and PI3K/AKT activities, an effect diminished by cell co-treatment with α-BTX, propranolol, and/or DhβE; and inhibited p53 activity in A549 cells, that was reversed, upon cell co-treatment with α-BTX, propranolol, and/or DhβE or by VEGF immunodepletion. VEGF levels increased upon cell treatment with nicotine, adrenaline/noradrenaline, and decreased with GABA treatment. On the other hand, the p53 activity decreased in A549 cells treated with nicotine, adrenaline/noradrenaline and increased upon cell incubation with GABA. Knockdown of p53 led to increased VEGF levels in the media of A549 cells. The addition of anti-VEGF antibodies to A549 and H1299 cells decreased cell viability and increased apoptosis; blocked the activities of PI3K, AKT, and NFκB in the absence or presence of nicotine; and resulted in increased p53 activation in A549 cells. We conclude that VEGF can be upregulated via α7nAChR and/or β-ARs and downregulated via GABA and/or p53 in response to the nicotine treatment of NSCLC cells.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Hedeel Guy Evans
- Chemistry Department, Eastern Michigan University, Ypsilanti, MI 48197, USA; (H.A.K.); (B.D.); (R.R.); (B.H.); (C.W.); (R.R.); (S.G.); (J.K.); (J.G.); (D.H.)
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Kalli M, Poskus MD, Stylianopoulos T, Zervantonakis IK. Beyond matrix stiffness: targeting force-induced cancer drug resistance. Trends Cancer 2023; 9:937-954. [PMID: 37558577 PMCID: PMC10592424 DOI: 10.1016/j.trecan.2023.07.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 06/27/2023] [Accepted: 07/13/2023] [Indexed: 08/11/2023]
Abstract
During tumor progression, mechanical abnormalities in the tumor microenvironment (TME) trigger signaling pathways in cells that activate cellular programs, resulting in tumor growth and drug resistance. In this review, we describe mechanisms of action for anti-cancer therapies and mechanotransduction programs that regulate cellular processes, including cell proliferation, apoptosis, survival and phenotype switching. We discuss how the therapeutic response is impacted by the three main mechanical TME abnormalities: high extracellular matrix (ECM) composition and stiffness; interstitial fluid pressure (IFP); and elevated mechanical forces. We also review drugs that normalize these abnormalities or block mechanosensors and mechanotransduction pathways. Finally, we discuss current challenges and perspectives for the development of new strategies targeting mechanically induced drug resistance in the clinic.
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Affiliation(s)
- Maria Kalli
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus
| | - Matthew D Poskus
- Department of Bioengineering and Hillman Cancer Center, University of Pittsburgh, PA, USA
| | - Triantafyllos Stylianopoulos
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.
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Moghbeli M, Taghehchian N, Akhlaghipour I, Samsami Y, Maharati A. Role of forkhead box proteins in regulation of doxorubicin and paclitaxel responses in tumor cells: A comprehensive review. Int J Biol Macromol 2023; 248:125995. [PMID: 37499722 DOI: 10.1016/j.ijbiomac.2023.125995] [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: 06/20/2023] [Revised: 07/18/2023] [Accepted: 07/24/2023] [Indexed: 07/29/2023]
Abstract
Chemotherapy is one of the common first-line therapeutic methods in cancer patients. Despite the significant effects in improving the quality of life and survival of patients, chemo resistance is observed in a significant part of cancer patients, which leads to tumor recurrence and metastasis. Doxorubicin (DOX) and paclitaxel (PTX) are used as the first-line drugs in a wide range of tumors; however, DOX/PTX resistance limits their use in cancer patients. Considering the DOX/PTX side effects in normal tissues, identification of DOX/PTX resistant cancer patients is required to choose the most efficient therapeutic strategy for these patients. Investigating the molecular mechanisms involved in DOX/PTX response can help to improve the prognosis in cancer patients. Several cellular processes such as drug efflux, autophagy, and DNA repair are associated with chemo resistance that can be regulated by transcription factors as the main effectors in signaling pathways. Forkhead box (FOX) family of transcription factor has a key role in regulating cellular processes such as cell differentiation, migration, apoptosis, and proliferation. FOX deregulations have been associated with resistance to chemotherapy in different cancers. Therefore, we discussed the role of FOX protein family in DOX/PTX response. It has been reported that FOX proteins are mainly involved in DOX/PTX response by regulation of drug efflux, autophagy, structural proteins, and signaling pathways such as PI3K/AKT, NF-kb, and JNK. This review is an effective step in introducing the FOX protein family as the reliable prognostic markers and therapeutic targets in cancer patients.
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Affiliation(s)
- Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Negin Taghehchian
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yalda Samsami
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Samavarchi Tehrani S, Esmaeili F, Shirzad M, Goodarzi G, Yousefi T, Maniati M, Taheri-Anganeh M, Anushiravani A. The critical role of circular RNAs in drug resistance in gastrointestinal cancers. Med Oncol 2023; 40:116. [PMID: 36917431 DOI: 10.1007/s12032-023-01980-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 02/20/2023] [Indexed: 03/16/2023]
Abstract
Nowadays, drug resistance (DR) in gastrointestinal (GI) cancers, as the main reason for cancer-related mortality worldwide, has become a serious problem in the management of patients. Several mechanisms have been proposed for resistance to anticancer drugs, including altered transport and metabolism of drugs, mutation of drug targets, altered DNA repair system, inhibited apoptosis and autophagy, cancer stem cells, tumor heterogeneity, and epithelial-mesenchymal transition. Compelling evidence has revealed that genetic and epigenetic factors are strongly linked to DR. Non-coding RNA (ncRNA) interferences are the most crucial epigenetic alterations explored so far, and among these ncRNAs, circular RNAs (circRNAs) are the most emerging members known to have unique properties. Due to the absence of 5' and 3' ends in these novel RNAs, the two ends are covalently bonded together and are generated from pre-mRNA in a process known as back-splicing, which makes them more stable than other RNAs. As far as the unique structure and function of circRNAs is concerned, they are implicated in proliferation, migration, invasion, angiogenesis, metastasis, and DR. A clear understanding of the molecular mechanisms responsible for circRNAs-mediated DR in the GI cancers will open a new window to the management of GI cancers. Hence, in the present review, we will describe briefly the biogenesis, multiple features, and different biological functions of circRNAs. Then, we will summarize current mechanisms of DR, and finally, discuss molecular mechanisms through which circRNAs regulate DR development in esophageal cancer, pancreatic cancer, gastric cancer, colorectal cancer, and hepatocellular carcinoma.
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Affiliation(s)
- Sadra Samavarchi Tehrani
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fataneh Esmaeili
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Moein Shirzad
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Golnaz Goodarzi
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Tooba Yousefi
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahmood Maniati
- Department of English, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mortaza Taheri-Anganeh
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran.
| | - Amir Anushiravani
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
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12
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Ren J, Hu Z, Niu G, Xia J, Wang X, Hong R, Gu J, Wang D, Ke C. Annexin A1 induces oxaliplatin resistance of gastric cancer through autophagy by targeting PI3K/AKT/mTOR. FASEB J 2023; 37:e22790. [PMID: 36786694 DOI: 10.1096/fj.202200400rr] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 12/29/2022] [Accepted: 01/12/2023] [Indexed: 02/15/2023]
Abstract
Resistance to oxaliplatin (OXA) is a major cause of recurrence in gastric cancer (GC) patients. Autophagy is an important factor ensuring the survival of cancer cells under chemotherapeutic stress. We aimed to investigate the role of OXA-related genes in autophagy and chemoresistance of gastric cancer cells. We established OXA-resistant gastric cancer cells and used RNA-seq to profile gene expression within OXA-resistant GC and corresponding parental cells. Immunohistochemistry and RT-qPCR was performed to detect gene expression in tissues of two cohorts of GC patients who received OXA-based chemotherapy. The chemoresistant effects of the gene were assessed by cell viability, apoptosis, and autophagy assays. The effects of the gene on autophagy were assessed with mRFP-GFP-LC3 and Western blotting (WB). Gene set enrichment analysis (GSEA) and WB were performed to detect the activity of PI3K/AKT/mTOR signaling under the regulation of the gene. The OXA-resistant property of GC cells is related to their enhanced autophagic activity. Based on RNA-seq profiling, ANXA1 was selected as a candidate, as it was upregulated significantly in OXA-resistant cells. Furthermore, we found that higher ANXA1 expression before chemotherapy was associated with subsequent development of resistance to oxaliplatin, and overexpression of ANXA1 promoted the resistance of gastric cancer cells to oxaliplatin. So, it may serve as a key regulator in GC chemo-resistance knockdown of ANXA1, via inhibiting autophagy, enhancing the sensitivity of OXA-resistant GC cells to OXA in vitro and in vivo. Mechanically, we identified that PI3K/AKT/mTOR signaling pathway was activated in the ANXA1 stable knockdown AGS/OXA cells, which leads to the suppression of autophagy. ANXA1 functions as a chemoresistant gene in GC cells by targeting the PI3K/AKT/mTOR signaling pathway and might be a prognostic predictor for GC patients who receive OXA-based chemotherapy.
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Affiliation(s)
- Jun Ren
- Department of General Surgery, Affiliated Shanghai Fifth People's Hospital, Fudan University, Shanghai, People's Republic of China.,Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, People's Republic of China.,General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou, People's Republic of China
| | - Zhiqing Hu
- Department of General Surgery, Affiliated Shanghai Fifth People's Hospital, Fudan University, Shanghai, People's Republic of China
| | - Gengming Niu
- Department of General Surgery, Affiliated Shanghai Fifth People's Hospital, Fudan University, Shanghai, People's Republic of China
| | - Jie Xia
- Department of General Surgery, Affiliated Shanghai Fifth People's Hospital, Fudan University, Shanghai, People's Republic of China
| | - Xing Wang
- Department of General Surgery, Affiliated Shanghai Fifth People's Hospital, Fudan University, Shanghai, People's Republic of China
| | - Runqi Hong
- Department of General Surgery, Affiliated Shanghai Fifth People's Hospital, Fudan University, Shanghai, People's Republic of China
| | - Jiawei Gu
- Department of General Surgery, Affiliated Shanghai Fifth People's Hospital, Fudan University, Shanghai, People's Republic of China
| | - Daorong Wang
- Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, People's Republic of China.,General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou, People's Republic of China
| | - Chongwei Ke
- Department of General Surgery, Affiliated Shanghai Fifth People's Hospital, Fudan University, Shanghai, People's Republic of China
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13
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3,3'-Diindolylmethane Augments 5-Fluorouracil-InducedGrowth Suppression in Gastric Cancer Cells through Suppression of the Akt/GSK-3 β and WNT/Beta-Catenin. JOURNAL OF ONCOLOGY 2023; 2023:8268955. [PMID: 36785670 PMCID: PMC9922186 DOI: 10.1155/2023/8268955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 12/23/2022] [Accepted: 12/26/2022] [Indexed: 02/09/2023]
Abstract
Gastric cancer (GC) is one of the most lethal cancers in South Korea, and it is a cancer of concern worldwide. 5-fluorouracil (5-Fu) is commonly used as the first-line therapy for advanced GC; however, its side effects often limit the dosage range and impair patients' quality of life. Due to the limitations of current chemotherapy, new anticancer therapies are urgently needed. 3,3'-diindolylmethane (DIM) has been reported to have the ability to protect against various types of cancer. Our study aimed to elucidate the anticancer effect of DIM in GC when treated with the chemotherapeutic agent 5-Fu. In our results, combined treatment with DIM and 5-Fu resulted in higher apoptosis and lower cell proliferation than treatment with 5-Fu in SNU484 and SNU638 cell lines. Furthermore, when DIM and 5-Fu were administered together, cell invasion was diminished by mediated E-cadherin, MMP-9, and uPA; p-Akt and p-GSK-3β levels were reduced more significantly than when 5-Fu was administered alone. Moreover, in the Wnt signaling pathway, combined treatment of DIM and 5-Fu diminished β-catenin levels in the nucleus and inhibited cyclin D1and c-Myc protein levels. The Akt inhibitor, wortmannin, further inhibited the levels of β-catenin and c-Myc that were inhibited by DIM and 5-Fu. Furthermore, an animal xenograft model demonstrated that DIM combined with 5-Fu considerably reduced tumor growth without any toxic effects by regulating the Akt/GSK-3β and β-catenin levels. Our findings suggest that DIM significantly potentiates the anticancer effects of 5-Fu by targeting the Akt/GSK-3β and WNT/β-catenin because the combination therapy is more effective than 5-Fu alone, thereby offering an innovative potential therapy for patients with GC.
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14
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Paccosi E, Balzerano A, Proietti-De-Santis L. Interfering with the Ubiquitin-Mediated Regulation of Akt as a Strategy for Cancer Treatment. Int J Mol Sci 2023; 24:ijms24032809. [PMID: 36769122 PMCID: PMC9917864 DOI: 10.3390/ijms24032809] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/26/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
The serine/threonine kinase Akt modulates the functions of numerous substrates, many of them being involved in cell proliferation and growth, metabolism, angiogenesis, resistance to hypoxia and migration. Akt is frequently deregulated in many types of human cancers, its overexpression or abnormal activation being associated with the increased proliferation and survival of cancer cells. A promising avenue for turning off the functionality of Akt is to either interfere with the K63-linked ubiquitination that is necessary for Akt membrane recruitment and activation or increase the K48-linked polyubiquitination that aims to target Akt to the proteasome for its degradation. Recent evidence indicates that targeting the ubiquitin proteasome system is effective for certain cancer treatments. In this review, the functions and roles of Akt in human cancer will be discussed, with a main focus on molecules and compounds that target various elements of the ubiquitination processes that regulate the activation and inactivation of Akt. Moreover, their possible and attractive implications for cancer therapy will be discussed.
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15
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Phosphorylation of IGFBP-3 by Casein Kinase 2 Blocks Its Interaction with Hyaluronan, Enabling HA-CD44 Signaling Leading to Increased NSCLC Cell Survival and Cisplatin Resistance. Cells 2023; 12:cells12030405. [PMID: 36766747 PMCID: PMC9913475 DOI: 10.3390/cells12030405] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/15/2023] [Accepted: 01/22/2023] [Indexed: 01/27/2023] Open
Abstract
Cisplatin is a platinum agent used in the treatment of non-small cell lung cancer (NSCLC). Much remains unknown regarding the basic operative mechanisms underlying cisplatin resistance in NSCLC. In this study, we found that phosphorylation of IGFBP-3 by CK2 (P-IGFBP-3) decreased its binding to hyaluronan (HA) but not to IGF-1 and rendered the protein less effective at reducing cell viability or increasing apoptosis than the non-phosphorylated protein with or without cisplatin in the human NSCLC cell lines, A549 and H1299. Our data suggest that blocking CD44 signaling augmented the effects of cisplatin and that IGFBP-3 was more effective at inhibiting HA-CD44 signaling than P-IGFBP-3. Blocking CK2 activity and HA-CD44 signaling increased cisplatin sensitivity and more effectively blocked the PI3K and AKT activities and the phospho/total NFκB ratio and led to increased p53 activation in A549 cells. Increased cell sensitivity to cisplatin was observed upon co-treatment with inhibitors targeted against PI3K, AKT, and NFκB while blocking p53 activity decreased A549 cell sensitivity to cisplatin. Our findings shed light on a novel mechanism employed by CK2 in phosphorylating IGFBP-3 and increasing cisplatin resistance in NSCLC. Blocking phosphorylation of IGFBP-3 by CK2 may be an effective strategy to increase NSCLC sensitivity to cisplatin.
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16
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Li Q, Li Z, Luo T, Shi H. Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy. MOLECULAR BIOMEDICINE 2022; 3:47. [PMID: 36539659 PMCID: PMC9768098 DOI: 10.1186/s43556-022-00110-2] [Citation(s) in RCA: 92] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 11/10/2022] [Indexed: 12/24/2022] Open
Abstract
The PI3K/AKT/mTOR and RAF/MEK/ERK pathways are commonly activated by mutations and chromosomal translocation in vital targets. The PI3K/AKT/mTOR signaling pathway is dysregulated in nearly all kinds of neoplasms, with the component in this pathway alternations. RAF/MEK/ERK signaling cascades are used to conduct signaling from the cell surface to the nucleus to mediate gene expression, cell cycle processes and apoptosis. RAS, B-Raf, PI3K, and PTEN are frequent upstream alternative sites. These mutations resulted in activated cell growth and downregulated cell apoptosis. The two pathways interact with each other to participate in tumorigenesis. PTEN alterations suppress RAF/MEK/ERK pathway activity via AKT phosphorylation and RAS inhibition. Several inhibitors targeting major components of these two pathways have been supported by the FDA. Dozens of agents in these two pathways have attracted great attention and have been assessed in clinical trials. The combination of small molecular inhibitors with traditional regimens has also been explored. Furthermore, dual inhibitors provide new insight into antitumor activity. This review will further comprehensively describe the genetic alterations in normal patients and tumor patients and discuss the role of targeted inhibitors in malignant neoplasm therapy. We hope this review will promote a comprehensive understanding of the role of the PI3K/AKT/mTOR and RAF/MEK/ERK signaling pathways in facilitating tumors and will help direct drug selection for tumor therapy.
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Affiliation(s)
- Qingfang Li
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, Chengdu, China
| | - Zhihui Li
- Department of Oncology, The General Hospital of Western Theater Command, Chengdu, PR China
| | - Ting Luo
- Department of Breast, Cancer Center, West China Hospital, Sichuan University, 610041, Chengdu, P. R. China.
| | - Huashan Shi
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, 610041, Chengdu, P. R. China.
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17
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Gao J, Yang S, Xie G, Pan J, Zhu F. Integrating Network Pharmacology and Experimental Verification to Explore the Pharmacological Mechanisms of Aloin Against Gastric Cancer. Drug Des Devel Ther 2022; 16:1947-1961. [PMID: 35757520 PMCID: PMC9232097 DOI: 10.2147/dddt.s360790] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/30/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose This study was designed to evaluate the pharmacological mechanisms of Aloin against gastric cancer (GC) via network pharmacology analysis combined with experimental verification. Methods Using network pharmacology methods, the potential targets of Aloin and targets related to GC were screened from public databases. The protein–protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to predict the core targets and pathways of Aloin against GC. The expressions of major targets predicted by network pharmacology in normal stomach tissues and GC tissues and their relationships with overall survival of GC were searched in GEPIA, HPA and DriverDBv3 database. The results of network pharmacology analysis were verified by in vitro experiments. Results A total of 129 potential targets were retrieved by searching the intersection of Aloin and GC targets. PPI network analysis indicated that 10 targets, including AKT1 and CASP3, were hub genes. GO enrichment analysis involved 93 biological processes, 19 cellular components, and 37 molecular functions. KEGG enrichment analysis indicated that the anti-cancer effect of Aloin was mediated through multiple pathways, such as PI3K-AKT, FoxO and Ras signaling pathway. Among them, the PI3K-AKT signaling pathway, which contained the largest number of enriched genes, may play a greater role in the treatment of GC. The validation of key targets in GEPIA, HPA and DriverDBv3 database showed that the verification results for most core genes were consistent with this study. Then, the results of in vitro experiment indicated that Aloin could inhibit proliferation of NCI-N87 cells and induce cell apoptosis. The results also showed that Aloin could decrease the mRNA and protein expressions of PI3K and AKT, suggesting that Aloin can treat GC by inducing cell apoptosis and regulating the PI3K-AKT signaling pathway. Conclusion This study identified the potential targets of Aloin against GC using network pharmacology and in vitro verification, which provided a new understanding of the pharmacological mechanisms of Aloin in treatment of GC.
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Affiliation(s)
- Jia Gao
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China
| | - Sifu Yang
- Medical Oncology Department, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, 310014, People’s Republic of China
| | - Guanqun Xie
- College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China
| | - Jieli Pan
- Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China
- Correspondence: Jieli Pan; Feiye Zhu, Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China, Email ;
| | - Feiye Zhu
- Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of China
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18
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Nanoparticle-based drug delivery systems to overcome gastric cancer drug resistance. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103231] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Luo H, Yi T, Huang D, Chen X, Li X, Wan Q, Huang H, Huang H, Wei H, Song Y, Que T, Hu R, Huang H, Luo K, Li C, Qin C, Zheng C, Lan C, Chen W, Zhou D, Luo Q. circ_PTN contributes to -cisplatin resistance in glioblastoma via PI3K/AKT signaling through the miR-542-3p/PIK3R3 pathway. MOLECULAR THERAPY - NUCLEIC ACIDS 2021; 26:1255-1269. [PMID: 34853725 PMCID: PMC8607136 DOI: 10.1016/j.omtn.2021.08.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 08/31/2021] [Indexed: 10/24/2022]
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20
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Khalafi S, Zhu S, Khurana R, Lohse I, Giordano S, Corso S, Al-Ali H, Brothers SP, Wahlestedt C, Schürer S, El-Rifai W. A novel strategy for combination of clofarabine and pictilisib is synergistic in gastric cancer. Transl Oncol 2021; 15:101260. [PMID: 34735897 PMCID: PMC8571525 DOI: 10.1016/j.tranon.2021.101260] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 10/08/2021] [Accepted: 10/25/2021] [Indexed: 12/24/2022] Open
Abstract
Drug sensitivity testing identified novel drugs like clofarabine effective in treating gastric cancer. mRNA sequencing can be used to identify agents with synergistic activity to a reference compound. Pictilisib sensitizes gastric cancer to clofarabine treatment through AKT inhibition. The combination of clofarabine and pictilisib inhibits tumor growth in cell lines and PDX models. Gastric cancer (GC) is frequently characterized by resistance to standard chemotherapeutic regimens and poor clinical outcomes. We aimed to identify a novel therapeutic approach using drug sensitivity testing (DST) and our computational SynerySeq pipeline. DST of GC cell lines was performed with a library of 215 Federal Drug Administration (FDA) approved compounds and identified clofarabine as a potential therapeutic agent. RNA-sequencing (RNAseq) of clofarabine treated GC cells was analyzed according to our SynergySeq pipeline and identified pictilisib as a potential synergistic agent. Clonogenic survival and Annexin V assays demonstrated increased cell death with clofarabine and pictilisib combination treatment (P<0.01). The combination induced double strand breaks (DSB) as indicated by phosphorylated H2A histone family member X (γH2AX) immunofluorescence and western blot analysis (P<0.01). Pictilisib treatment inhibited the protein kinase B (AKT) cell survival pathway and promoted a pro-apoptotic phenotype as evidenced by quantitative real time polymerase chain reaction (qRT-PCR) analysis of the B-cell lymphoma 2 (BCL2) protein family members (P<0.01). Patient derived xenograft (PDX) data confirmed that the combination is more effective in abrogating tumor growth with prolonged survival than single-agent treatment (P<0.01). The novel combination of clofarabine and pictilisib in GC promotes DNA damage and inhibits key cell survival pathways to induce cell death beyond single-agent treatment.
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Affiliation(s)
- Shayan Khalafi
- Department of Surgery, Miller School of Medicine, University of Miami, Rosenstiel Medical Science Bldg, 1600 NW 10th Ave, Room 4007, Miami, FL 33136-1015, United States
| | - Shoumin Zhu
- Department of Surgery, Miller School of Medicine, University of Miami, Rosenstiel Medical Science Bldg, 1600 NW 10th Ave, Room 4007, Miami, FL 33136-1015, United States; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, United States
| | - Rimpi Khurana
- Department of Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33136, United States
| | - Ines Lohse
- Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Molecular Therapeutics Shared Resource, Sylvester Comprehensive Cancer Center, University of Miami, FL 33136, United States
| | - Silvia Giordano
- Department of Oncology, University of Torino, Candiolo 10060, Italy; Candiolo Cancer Institute, FPO-IRCCS, Candiolo 10060, Italy
| | - Simona Corso
- Department of Oncology, University of Torino, Candiolo 10060, Italy; Candiolo Cancer Institute, FPO-IRCCS, Candiolo 10060, Italy
| | - Hassan Al-Ali
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Peggy and Harold Katz Drug Discovery Center, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136, United States
| | - Shaun P Brothers
- Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, United States
| | - Claes Wahlestedt
- Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, United States
| | - Stephan Schürer
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Institute for Data Science and Computing, University of Miami, Miami, FL 33136, United States
| | - Wael El-Rifai
- Department of Surgery, Miller School of Medicine, University of Miami, Rosenstiel Medical Science Bldg, 1600 NW 10th Ave, Room 4007, Miami, FL 33136-1015, United States; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Veterans Affairs, Miami Healthcare System, Miami, FL 33136, United States.
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21
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Xu Y, Hu Y, Xu T, Yan K, Zhang T, Li Q, Chang F, Guo X, Peng J, Li M, Zhao M, Zhen H, Xu L, Zheng D, Li L, Shao G. RNF8-mediated regulation of Akt promotes lung cancer cell survival and resistance to DNA damage. Cell Rep 2021; 37:109854. [PMID: 34686341 DOI: 10.1016/j.celrep.2021.109854] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 08/18/2021] [Accepted: 09/28/2021] [Indexed: 01/21/2023] Open
Abstract
Despite the tremendous success of targeted and conventional therapies for lung cancer, therapeutic resistance is a common and major clinical challenge. RNF8 is a ubiquitin E3 ligase that plays essential roles in the DNA damage response; however, its role in the pathogenesis of lung cancer is unclear. Here, we report that RNF8 is overexpressed in lung cancer and positively correlates with the expression of p-Akt and poor survival of patients with non-small-cell lung cancer. In addition, we identify RNF8 as the E3 ligase for regulating the activation of Akt by K63-linked ubiquitination under physiological and genotoxic conditions, which leads to lung cancer cell proliferation and resistance to chemotherapy. Together, our study suggests that RNF8 could be a very promising target in precision medicine for lung cancer.
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Affiliation(s)
- Yongjie Xu
- Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Yumeng Hu
- Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Tao Xu
- The Affiliated Hospital of Qingdao University, Qingdao 266021, China
| | - Kaowen Yan
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Ting Zhang
- Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Qin Li
- Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Fen Chang
- Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Xueyuan Guo
- Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Jingyu Peng
- State Key Laboratory of Membrane Biology, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing 100871, China
| | - Mo Li
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
| | - Min Zhao
- Department of Oncology, Hebei Chest Hospital, Research Center of Hebei Lung Cancer Prevention and Treatment, Shijiazhuang, Hebei 050041, China
| | - Hongying Zhen
- Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Luzheng Xu
- Medical and Health Analysis Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Duo Zheng
- Department of Cell Biology and Genetics, Shenzhen University School of Medicine, Shenzhen 518055, China
| | - Li Li
- Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
| | - Genze Shao
- Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
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22
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Sopha P, Phutubtim N, Chantrathonkul B, Ploypradith P, Ruchirawat S, Chittchang M. Roles of autophagy in relation to mitochondrial stress responses of HeLa cells to lamellarin cytotoxicity. Toxicology 2021; 462:152963. [PMID: 34560126 DOI: 10.1016/j.tox.2021.152963] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/13/2021] [Accepted: 09/20/2021] [Indexed: 12/14/2022]
Abstract
As a promising class of bioactive marine pyrrole alkaloids, lamellarins reportedly act on multiple targets to suppress the vitality of various cancer cell lines. Nevertheless, an in-depth understanding of the molecular mechanisms governing their cytotoxicity is still in demand. Here we report that while activating intrinsic apoptosis, up to 5 μM of lamellarins and their lactam-containing analogs, azalamellarins, also induced mitochondrial stress responses and autophagy in HeLa cervical cancer cells. Detailed characterization of the mitochondria in the treated cells revealed shifted abundance of the two optic atrophy protein 1 (Opa1) isoforms, disturbed morphology, and dissipated membrane potential, leading to PTEN-induced kinase-1 (PINK1) and microtubule-associated protein 1 light chain 3-II (LC3-II) accumulation as a molecular signature of mitophagy. Furthermore, an acute treatment with lamellarins also modulated cellular autophagy flux as evidenced by elevated LC3-II levels, LC3 puncta formation, and p62 degradation. Surprisingly, clustered regularly interspaced short palindromic repeats (CRISPR)-based suppression of autophagy transiently affected the number of apoptotic cells induced by these compounds. Our findings illustrate the potential of these alkaloids for further development into prospective anti-cancer agents.
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Affiliation(s)
- Pattarawut Sopha
- Program in Applied Biological Sciences, Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6 Road, Lak Si, Bangkok 10210, Thailand; The Center of Excellence on Environmental Health and Toxicology (EHT), Rama VI Road, Ratchathewi, Bangkok 10400, Thailand.
| | - Nadgrita Phutubtim
- Program in Applied Biological Sciences, Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6 Road, Lak Si, Bangkok 10210, Thailand; Research Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6 Road, Lak Si, Bangkok 10210, Thailand
| | - Bunkuea Chantrathonkul
- Research Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6 Road, Lak Si, Bangkok 10210, Thailand
| | - Poonsakdi Ploypradith
- Program in Chemical Sciences, Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6 Road, Lak Si, Bangkok 10210, Thailand; The Center of Excellence on Environmental Health and Toxicology (EHT), Rama VI Road, Ratchathewi, Bangkok 10400, Thailand; Research Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6 Road, Lak Si, Bangkok 10210, Thailand
| | - Somsak Ruchirawat
- Program in Chemical Sciences, Chulabhorn Graduate Institute, 54 Kamphaeng Phet 6 Road, Lak Si, Bangkok 10210, Thailand; The Center of Excellence on Environmental Health and Toxicology (EHT), Rama VI Road, Ratchathewi, Bangkok 10400, Thailand; Research Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6 Road, Lak Si, Bangkok 10210, Thailand
| | - Montakarn Chittchang
- The Center of Excellence on Environmental Health and Toxicology (EHT), Rama VI Road, Ratchathewi, Bangkok 10400, Thailand; Research Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6 Road, Lak Si, Bangkok 10210, Thailand.
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23
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Zangouei AS, Moghbeli M. MicroRNAs as the critical regulators of cisplatin resistance in gastric tumor cells. Genes Environ 2021; 43:21. [PMID: 34099061 PMCID: PMC8182944 DOI: 10.1186/s41021-021-00192-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 05/24/2021] [Indexed: 12/13/2022] Open
Abstract
Combined chemotherapeutic treatment is the method of choice for advanced and metastatic gastric tumors. However, resistance to chemotherapeutic agents is one of the main challenges for the efficient gastric cancer (GC) treatment. Cisplatin (CDDP) is used as an important regimen of chemotherapy for GC which induces cytotoxicity by interfering with DNA replication in cancer cells and inducing their apoptosis. Majority of patients experience cisplatin-resistance which is correlated with tumor metastasis and relapse. Moreover, prolonged and high-dose cisplatin administrations cause serious side effects such as nephrotoxicity, ototoxicity, and anemia. Since, there is a high rate of recurrence after CDDP treatment in GC patients; it is required to clarify the molecular mechanisms associated with CDDP resistance to introduce novel therapeutic methods. There are various cell and molecular processes associated with multidrug resistance (MDR) including drug efflux, detoxification, DNA repair ability, apoptosis alteration, signaling pathways, and epithelial-mesenchymal transition (EMT). MicroRNAs are a class of endogenous non-coding RNAs involved in chemo resistance of GC cells through regulation of all of the MDR mechanisms. In present review we have summarized all of the miRNAs associated with cisplatin resistance based on their target genes and molecular mechanisms in gastric tumor cells. This review paves the way of introducing a miRNA-based panel of prognostic markers to improve the efficacy of chemotherapy and clinical outcomes in GC patients. It was observed that miRNAs are mainly involved in cisplatin response of gastric tumor cells via regulation of signaling pathways, autophagy, and apoptosis.
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Affiliation(s)
- Amir Sadra Zangouei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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24
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Li M, Shan W, Hua Y, Chao F, Cui Y, Lv L, Dou X, Bian X, Zou J, Li H, Lin W. Exosomal miR-92b-3p Promotes Chemoresistance of Small Cell Lung Cancer Through the PTEN/AKT Pathway. Front Cell Dev Biol 2021; 9:661602. [PMID: 34136482 PMCID: PMC8201786 DOI: 10.3389/fcell.2021.661602] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 04/19/2021] [Indexed: 12/13/2022] Open
Abstract
Resistance to first-line chemotherapy drugs has become an obstacle to improving the clinical prognosis of patients with small cell lung cancer (SCLC). Exosomal microRNAs have been shown to play pro- and anti-chemoresistant roles in various cancers, but their role in SCLC chemoresistance has never been explored. In this study, we observed that the expression of exosomal miR-92b-3p was significantly increased in patients who developed chemoresistance. Luciferase reporter analysis confirmed that PTEN was a target gene of miR-92b-3p. The PTEN/AKT regulatory network was related to miR-92b-3p-mediated cell migration and chemoresistance in vitro and in vivo in SCLC. Importantly, exosomes isolated from the conditioned medium of SBC-3 cells overexpressing miR-92b-3p could promote SCLC chemoresistance and cell migration. Furthermore, we found that plasma miR-92b-3p levels were significantly higher in patients with chemoresistant SCLC than in those with chemosensitive SCLC, but the levels were down-regulated in patients who achieved remission. Kaplan–Meier analysis showed that SCLC patients with high miR-92b-3p expression were associated with shorter progression-free survival. Overall, our results suggested that exosomal miR-92b-3p is a potential dynamic biomarker to monitor chemoresistance in SCLC and represents a promising therapeutic target for chemoresistant SCLC.
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Affiliation(s)
- Ming Li
- Department of Laboratory Diagnostics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Wulin Shan
- Department of Laboratory Diagnostics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yan Hua
- Department of Laboratory Diagnostics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Fengmei Chao
- Department of Laboratory Diagnostics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yayun Cui
- Department of Laboratory Diagnostics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Lei Lv
- Department of Laboratory Diagnostics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Xiaoyan Dou
- Department of Laboratory Diagnostics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Xing Bian
- High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China.,Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
| | - Jinglu Zou
- High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China.,Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
| | - Hong Li
- High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China.,Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
| | - Wenchu Lin
- High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China.,Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China
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25
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Zhou Y, Sha Z, Yang Y, Wu S, Chen H. lncRNA NEAT1 regulates gastric carcinoma cell proliferation, invasion and apoptosis via the miR‑500a‑3p/XBP‑1 axis. Mol Med Rep 2021; 24:503. [PMID: 33982777 PMCID: PMC8134875 DOI: 10.3892/mmr.2021.12142] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 02/15/2021] [Indexed: 12/30/2022] Open
Abstract
Gastric cancer is a serious malignant tumor. Despite progression in gastric cancer research in recent years, the specific molecular mechanism underlying the pathogenesis of the disease is not completely understood. Long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) affects the proliferation and metastasis of multiple types of tumor cells in colorectal cancer and breast cancer but its specific role in gastric cancer requires further investigation. The aim of the present study was to analyze the role of NEAT1 in gastric cancer. The expression of endoplasmic reticulum stress marker proteins and apoptosis-related proteins in gastric cancer tissue and cell lines was analyzed using western blotting. The targeting relationship of NEAT1 and miR-500a-3p was analyzed using dual-luciferase reporter assay. Cell proliferation was analyzed using CCK8 assay and colony formation assay while cell invasion was detected using Transwell assay. Cell apoptosis was analyzed using TUNEL staining and LC3 expression through immunofluorescent staining (IF). The results showed that lncRNA NEAT1-overexpression gastric cancer cells were established to determine its effects on cell proliferation, invasion, apoptosis, autophagy and endoplasmic reticulum stress. Subsequently, microRNA (miR)-500a was overexpressed in lncRNA NEAT1-overexpression cells. Compared with the vector group, lncRNA NEAT1 overexpression significantly inhibited gastric cancer cell proliferation and invasion, but significantly promoted cell apoptosis. Furthermore, the results indicated that lncRNA NEAT1 targeted and downregulated the expression of miR-500a-3p, and miR-500a-3p targeted X-box binding protein-1 (XBP-1) mRNA. lncRNA NEAT1 overexpression-mediated inhibition of gastric cancer cell proliferation and invasion was significantly reversed by miR-500a-3p overexpression. Furthermore, compared with the vector group, the expression levels of endoplasmic reticulum stress-related proteins (XBP-1S/XBP-1U ratio and 78-kDa glucose-regulated protein) and apoptosis-related proteins (Bax and cleaved-caspase-3) were significantly upregulated by lncRNA NEAT1 overexpression; however, miR-500a-3p overexpression reversed lncRNA NEAT1 overexpression-mediated effects on protein expression. The present study demonstrated that lncRNA NEAT1 inhibited gastric cancer cell proliferation and invasion, and promoted apoptosis by regulating the miR-500a-3p/XBP-1 axis.
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Affiliation(s)
- Yun Zhou
- Department of Gastroenterology, Zhongda Hospital Southeast University, Medical College of Southeast University, Nanjing, Jiangsu 210000, P.R. China
| | - Zhenghong Sha
- Department of General Surgery, Wuhu No. 1 People's Hospital, Wuhu, Anhui 241000, P.R. China
| | - Yong Yang
- Department of Gastroenterology, Wuhu No. 1 People's Hospital, Wuhu, Anhui 241000, P.R. China
| | - Shuimei Wu
- Department of Gastroenterology, Wuhu No. 1 People's Hospital, Wuhu, Anhui 241000, P.R. China
| | - Hong Chen
- Department of Gastroenterology, Zhongda Hospital Southeast University, Medical College of Southeast University, Nanjing, Jiangsu 210000, P.R. China
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26
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Liu C, Wu H, Mao Y, Chen W, Chen S. Exosomal microRNAs in hepatocellular carcinoma. Cancer Cell Int 2021; 21:254. [PMID: 33964930 PMCID: PMC8106840 DOI: 10.1186/s12935-021-01941-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 04/19/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma is one of the most common malignant tumors worldwide and the fourth leading cause of cancer-related deaths. The prognosis of hepatocellular carcinoma patients is extremely poor due to the occult onset and high metastasis of hepatocellular carcinoma. Therefore, biomarkers with high specificity and sensitivity are of great importance in early screening, diagnosis prognosis, and treatment of hepatocellular carcinoma patients. Exosomes are tiny vesicles secreted by various types of cells, which can serve as mediators of intercellular communication to regulate the tumor microenvironment, and play a key role in the occurrence, development, prognosis, monitor and treatment of hepatocellular carcinoma. As microRNA deliverer, exosomes are involved in multiple life activities by regulating target genes of recipient cells such as proliferation, invasion, metastasis and apoptosis of cancer cells. In this review, we summarized the composition, active mechanism and function of exosomal microRNAs in hepatocellular carcinoma, and elaborated on their potential application value of early diagnosis and treatment in hepatocellular carcinoma.
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Affiliation(s)
- Chenbin Liu
- School of Medicine, Shanghai Jiao Tong University, 227 Chongqing South Road, Shanghai, 200025, China
| | - Han Wu
- School of Medicine, Shanghai Jiao Tong University, 227 Chongqing South Road, Shanghai, 200025, China
| | - Yinqi Mao
- School of Medicine, Shanghai Jiao Tong University, 227 Chongqing South Road, Shanghai, 200025, China
| | - Wei Chen
- School of Medicine, Shanghai Jiao Tong University, 227 Chongqing South Road, Shanghai, 200025, China
| | - Shuying Chen
- Department of Laboratory Medicine, Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, Shanghai, 200040, China.
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27
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Wei X, Shi J, Lin Q, Ma X, Pang Y, Mao H, Li R, Lu W, Wang Y, Liu P. Targeting ACLY Attenuates Tumor Growth and Acquired Cisplatin Resistance in Ovarian Cancer by Inhibiting the PI3K-AKT Pathway and Activating the AMPK-ROS Pathway. Front Oncol 2021; 11:642229. [PMID: 33816292 PMCID: PMC8011496 DOI: 10.3389/fonc.2021.642229] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 02/23/2021] [Indexed: 01/19/2023] Open
Abstract
Background: Ovarian cancer is the most lethal female genital malignancy. Although cisplatin is the first-line chemotherapy to treat ovarian cancer patients along with debulking surgeries, its efficacy is limited due to the high incidence of cisplatin resistance. ATP citrate lyase (ACLY) has been shown to be a key metabolic enzyme and is associated with poor prognosis in various cancers, including ovarian cancer. Nevertheless, no studies have probed the mechanistic relationship between ACLY and cisplatin resistance. Methods: Survival analysis was mainly carried out online. Bioinformatic analysis was performed in R/R studio. Proliferative activity was measured by MTT and colony formation assays. Cell cycle and apoptosis analysis were performed by flow cytometry. The acquired-cisplatin-resistant cell line A2780/CDDP was generated by exposing A2780 to cisplatin at gradually elevated concentrations. MTT assay was used to calculate IC50 values of cisplatin. A xenograft tumor assay was used test cell proliferation in vivo. Results: Higher expression of ACLY was found in ovarian cancer tissue and related to poor prognosis. Knockdown of ACLY in A2780, SKOV3, and HEY cells inhibited cell proliferation, caused cell-cycle arrest by modulating the P16–CDK4–CCND1 pathway, and induced apoptosis probably by inhibiting p-AKT activity. Bioinformatic analysis of the GSE15709 dataset revealed upregulation of ACLY and activation of PI3K–AKT pathway in cells with acquired cisplatin resistance, in line with observations on A2780/CDDP cells that we generated. Knockdown of ACLY alleviated cisplatin resistance, and works synergistically with cisplatin treatment to induce apoptosis in A2780/CDDP cells by inhibiting the PI3K–AKT pathway and activating AMPK–ROS pathway. The ACLY-specific inhibitor SB-204990 showed the same effect. In A2780/CDDP cells, AKT overexpression could attenuate cisplatin re-sensitization caused by ACLY knockdown. Conclusions: Knockdown of ACLY attenuated cisplatin resistance by inhibiting the PI3K–AKT pathway and activating the AMPK–ROS pathway. These findings suggest that a combination of ACLY inhibition and cisplatin might be an effective strategy for overcoming cisplatin resistance in ovarian cancer.
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Affiliation(s)
- Xuan Wei
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.,Key Laboratory of Gynecology Oncology of Shandong Province, Qilu Hospital of Shandong University, Jinan, China.,Shandong Engineering Laboratory for Urogynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Juanjuan Shi
- Department of Gynecology and Obstetrics, Affiliated Tengzhou Center People's Hospital of Jining Medical University, Tengzhou, China
| | - Qianhan Lin
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.,Key Laboratory of Gynecology Oncology of Shandong Province, Qilu Hospital of Shandong University, Jinan, China.,Shandong Engineering Laboratory for Urogynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Xiaoxue Ma
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.,Key Laboratory of Gynecology Oncology of Shandong Province, Qilu Hospital of Shandong University, Jinan, China.,Shandong Engineering Laboratory for Urogynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Yingxin Pang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.,Key Laboratory of Gynecology Oncology of Shandong Province, Qilu Hospital of Shandong University, Jinan, China.,Shandong Engineering Laboratory for Urogynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Hongluan Mao
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.,Key Laboratory of Gynecology Oncology of Shandong Province, Qilu Hospital of Shandong University, Jinan, China.,Shandong Engineering Laboratory for Urogynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Rui Li
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.,Key Laboratory of Gynecology Oncology of Shandong Province, Qilu Hospital of Shandong University, Jinan, China.,Shandong Engineering Laboratory for Urogynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Wei Lu
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.,Key Laboratory of Gynecology Oncology of Shandong Province, Qilu Hospital of Shandong University, Jinan, China.,Shandong Engineering Laboratory for Urogynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Yu Wang
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.,Key Laboratory of Gynecology Oncology of Shandong Province, Qilu Hospital of Shandong University, Jinan, China.,Shandong Engineering Laboratory for Urogynecology, Qilu Hospital of Shandong University, Jinan, China
| | - Peishu Liu
- Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.,Key Laboratory of Gynecology Oncology of Shandong Province, Qilu Hospital of Shandong University, Jinan, China.,Shandong Engineering Laboratory for Urogynecology, Qilu Hospital of Shandong University, Jinan, China
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28
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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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29
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Zhang H, Zhang LQ, Yang CC, Li J, Tian XY, Li DN, Cui J, Cai JP. The high expression of NUDT5 indicates poor prognosis of breast cancer by modulating AKT / Cyclin D signaling. PLoS One 2021; 16:e0245876. [PMID: 33571243 PMCID: PMC7877577 DOI: 10.1371/journal.pone.0245876] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 01/08/2021] [Indexed: 11/24/2022] Open
Abstract
NUDIX hydrolase type 5 (NUDT5) is a kind of ADP-ribose pyrophosphatase and nucleotide metabolizing enzyme in cell metabolism. Previous studies have shown NUDT5 expression affected chromosome remodeling, involved in cell adhesion, cancer stem cell maintenance and epithelial to mesenchyme transition in breast cancer cells. Nevertheless, the role of NUDT5 in breast cancer progression and prognosis has not yet been systematically studied. This study explored the association of NUDT5 with the tumor development and poor prognosis in patients with breast cancer. Our results show that the levels of NUDT5 were upregulated in breast cancer cell lines and breast tumor tissues, and the expression of NUDT5 in breast tumor tissues increased significantly when compared with adjacent non-tumorous tissues by immunohistochemical staining of tissue microarrays. Breast cancer patients with high NUDT5 expression had a worse prognosis than those with low expression of NUDT5. In addition, the knockdown of NUDT5 suppressed breast cancer cell lines proliferation, migration and invasion, and dramatically inhibited the AKT phosphorylation at Thr308 and expression of Cyclin D1. The opposite effects were observed in vitro following NUDT5 rescue. Our findings indicated that the high expression of NUDT5 is probably involved in the poor prognosis of breast cancer via the activation of the AKT / Cyclin D pathways, which could be a prognostic factor and potential target in the diagnosis and treatment of breast cancer.
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Affiliation(s)
- He Zhang
- Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Dongdan, Beijing, P.R China
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Dong Dan, Beijing, P.R. China
- Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Dong Dan, Beijing, P.R. China
| | - Li-Qun Zhang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Dong Dan, Beijing, P.R. China
| | - Cheng-Cheng Yang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Dong Dan, Beijing, P.R. China
- Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Dong Dan, Beijing, P.R. China
- Department of Pharmacy, Wenzhou Medical College, Wenzhou, Zhejiang, P.R China
| | - Jin Li
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Dong Dan, Beijing, P.R. China
- Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Dong Dan, Beijing, P.R. China
| | - Xin-Yuan Tian
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Dong Dan, Beijing, P.R. China
- Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Dong Dan, Beijing, P.R. China
- Peking University Fifth School of Clinical Medicine, Beijing Hospital, Beijing, P.R. China
| | - Dan-Ni Li
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Dong Dan, Beijing, P.R. China
- Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Dong Dan, Beijing, P.R. China
- Peking University Fifth School of Clinical Medicine, Beijing Hospital, Beijing, P.R. China
| | - Ju Cui
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Dong Dan, Beijing, P.R. China
- Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Dong Dan, Beijing, P.R. China
| | - Jian-Ping Cai
- Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Dongdan, Beijing, P.R China
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Dong Dan, Beijing, P.R. China
- Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Dong Dan, Beijing, P.R. China
- * E-mail:
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30
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Li C, Zhao J, Sun W. microRNA-222-Mediated VHL Downregulation Facilitates Retinoblastoma Chemoresistance by Increasing HIF1α Expression. Invest Ophthalmol Vis Sci 2021; 61:9. [PMID: 32756923 PMCID: PMC7441340 DOI: 10.1167/iovs.61.10.9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Purpose Retinoblastoma (RB) is the most common primary intraocular tumor in children. Chemoresistance is the major obstacle for treatment of these tumors. This study aims to determine whether or not downregulating microRNA-222 (miR-222) could serve as a potential therapeutic target for preventing chemoresistance in RB treatment. Methods Differentially expressed miR-222 in RB samples and its downstream target genes were predicted using bioinformatics methods. The expression of miR-222 was altered by mimic or inhibitor to examine its role in RB cell in response to the chemotherapeutic agent vincristine (VCR). Further bioinformatic analysis predicted involvement of the stability of hypoxia-inducible factor 1α (HIF1α) protein in regulation of the von Hippel–Lindau (VHL) tumor suppressor, followed by characterization of the effect of VHL on the ubiquitin–proteasome degradation of HIF1α. Next, VHL or HIF1α was overexpressed to determine their effects on RB cell activities after VCR treatment. In vivo assays were performed on nude mice to further verify the in vitro results. Results miR-222 is highly expressed in RB tissues and cells and was found to facilitate resistance of RB cells to VCR. Of note, miR-222 specifically bound to and negatively regulated VHL. VHL could inhibit the stability of HIF1α and promote the degradation of ubiquitin–proteasome, thus reducing HIF1α expression to attenuate VCR resistance in RB cells. Moreover, inhibition of miR-222 in combination with VCR suppressed tumor formation in nude mice. Conclusions miR-222 promotes the expression of HIF1α by targeting VHL, thus accelerating the resistance of RB cells to the chemotherapeutic agent VCR.
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Affiliation(s)
- Chunzhi Li
- Department of Pharmacy, Linyi People's Hospital, Linyi, China
| | - Jun Zhao
- Department of Ophthalmology, Linyi People's Hospital, Linyi, China
| | - Weiying Sun
- Department of Pharmacy, Linyi People's Hospital, Linyi, China
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31
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Fattahi S, Amjadi-Moheb F, Tabaripour R, Ashrafi GH, Akhavan-Niaki H. PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond. Life Sci 2020; 262:118513. [PMID: 33011222 DOI: 10.1016/j.lfs.2020.118513] [Citation(s) in RCA: 236] [Impact Index Per Article: 47.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 09/22/2020] [Accepted: 09/22/2020] [Indexed: 02/07/2023]
Abstract
PI3K/AKT/mTOR pathway is one of the most important signaling pathways involved in normal cellular processes. Its aberrant activation modulates autophagy, epithelial-mesenchymal transition, apoptosis, chemoresistance, and metastasis in many human cancers. Emerging evidence demonstrates that some infections as well as epigenetic regulatory mechanisms can control PI3K/AKT/mTOR signaling pathway. In this review, we focused on the role of this pathway in gastric cancer development, prognosis, and metastasis, with an emphasis on epigenetic alterations including DNA methylation, histone modifications, and post-transcriptional modulations through non-coding RNAs fluctuations as well as H. pylori and Epstein-Barr virus infections. Finally, we reviewed different molecular targets and therapeutic agents in clinical trials as a potential strategy for gastric cancer treatment through the PI3K/AKT/mTOR pathway.
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Affiliation(s)
- Sadegh Fattahi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran; Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; North Research Center, Pasteur Institute, Amol, Iran
| | - Fatemeh Amjadi-Moheb
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Reza Tabaripour
- Department of Cellular and Molecular Biology, Islamic Azad University Babol-Branch, Iran
| | - Gholam Hossein Ashrafi
- Kingston University London, Cancer theme, School of Life Science, Pharmacy and Chemistry, SEC Faculty, Kingston upon Thames, KT12EE, London, UK
| | - Haleh Akhavan-Niaki
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran.
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Al-Bahlani S, Burney IA, Al-Dhahli B, Al-Kharusi S, Al-Kharousi F, Al-Kalbani A, Ahmed I. Boswellic acid sensitizes gastric cancer cells to Cisplatin-induced apoptosis via p53-mediated pathway. BMC Pharmacol Toxicol 2020; 21:64. [PMID: 32867831 PMCID: PMC7460741 DOI: 10.1186/s40360-020-00442-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 08/25/2020] [Indexed: 12/18/2022] Open
Abstract
Background Cisplatin (CDDP) is an effective anticancer drug for Gastric cancer (GC) that induces apoptosis by altering pro- (p53) and anti-apoptotic (Akt and NFkB) proteins; however, chemoresistance remains a big challenge. Additional compounds with promising anticancer effects such as AKBA (Acetyl-keto-beta boswellic acid) may overcome the resistance. However, its role in CDDP-induced apoptosis in GC has not been studied. This study aimed to examine the effectiveness of AKBA on p53-mediated, CDDP-induced apoptosis in GC cells. AGS and NCI-N87 cells were treated with different concentrations (0, 25, 50, 100 μM) of CDDP and/or AKBA. Methods P53, Akt and NFkB proteins and apoptosis were assessed by Western blot and flow cytometry. The role of p53 was determined by inhibiting its function via the siRNA approach. Results The results revealed that CDDP and AKBA significantly increased p53 content in both cells, while Akt and NFkB were significantly decreased. Both compounds significantly induced apoptosis in a dose-dependent manner. AKBA sensitized GC cells to CDDP-induced apoptosis by altering the protein expression. P53 downregulation affected Akt and NFkB proteins with a slight increase in apoptosis induction in the combination treated groups. Conclusions Altogether, our findings suggest that AKBA enhances GC cell sensitivity to CDDP-induced apoptosis via the p53 pathway.
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Affiliation(s)
- Shadia Al-Bahlani
- Department of Allied Health Sciences, College of Medicine and Health Sciences, Sultan Qaboos University, P. O. Box 35, PC 123 AlKhoud, Muscat, Oman.
| | - Ikram A Burney
- Department of Medicine, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - Buthaina Al-Dhahli
- Department of Allied Health Sciences, College of Medicine and Health Sciences, Sultan Qaboos University, P. O. Box 35, PC 123 AlKhoud, Muscat, Oman
| | - Safiya Al-Kharusi
- Department of Allied Health Sciences, College of Medicine and Health Sciences, Sultan Qaboos University, P. O. Box 35, PC 123 AlKhoud, Muscat, Oman
| | - Fakhra Al-Kharousi
- Department of Allied Health Sciences, College of Medicine and Health Sciences, Sultan Qaboos University, P. O. Box 35, PC 123 AlKhoud, Muscat, Oman
| | - Amani Al-Kalbani
- Department of Allied Health Sciences, College of Medicine and Health Sciences, Sultan Qaboos University, P. O. Box 35, PC 123 AlKhoud, Muscat, Oman
| | - Ikhlas Ahmed
- Department of Pharmacology and Clinical Pharmacy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
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MAC30 Knockdown Inhibits Proliferation and Enhance Apoptosis of Gastric Cancer by Suppressing Wnt/ β-Cateninsignaling Pathway. Gastroenterol Res Pract 2020; 2020:6358685. [PMID: 32904598 PMCID: PMC7456481 DOI: 10.1155/2020/6358685] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 07/15/2020] [Indexed: 01/17/2023] Open
Abstract
Gastric cancer is one of the most frequently diagnosed cancer and poses a serious threat to health system in the world. Upregulation of meningioma-associated protein (MAC30) has been found in many solid tumors and can regulate the proliferation, differentiation, and apoptosis of different tumor cells. Quantitative polymerase chain reaction (qPCR) was used to detect the expression of MAC30 in 68 patients with gastric cancer and their adjacent tissues. Lentiviral vector pGCSIL-shMAC30-GFP of the RNA interference (RNAi) of the MAC30 gene was transfected into gastric cancer BGC-823 cell line and the expression of lentivirus label protein GFP was observed via fluorescence microscope, while cell proliferation and apoptosis were determined with flow cytometry and MTT assay, respectively. Also, related protein expressions on Wnt/β-catenin signaling pathway were analyzed by Western blot method. The expression of MAC30 was abnormally elevated in gastric cancer tissues, while interfering of its expression could significantly inhibit the proliferation of gastric cancer BGC-823 cell line. However, the promotion of apoptosis by mitochondrial pathway was mediated by Bax/Bcl-2 upregulation. Present work showed the effect of downregulated MAC30 expression on proliferation and apoptosis of gastric cancer cell through Wnt/β-catenin signaling pathway. Thus, this investigation provides an experimental basis for future development of chemotherapeutic agent on gastric cancer.
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Wei Z, Liu G, Jia R, Zhang W, Li L, Zhang Y, Wang Z, Bai X. Targeting secretory leukocyte protease inhibitor (SLPI) inhibits colorectal cancer cell growth, migration and invasion via downregulation of AKT. PeerJ 2020; 8:e9400. [PMID: 32742768 PMCID: PMC7367054 DOI: 10.7717/peerj.9400] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 06/01/2020] [Indexed: 12/21/2022] Open
Abstract
The secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor which plays important role in bacterial infection, inflammation, wound healing and epithelial proliferation. Dysregulation of SLPI has been reported in a variety of human cancers including glioblastoma, lung, breast, ovarian and colorectal carcinomas and is associated with tumor aggressiveness and metastatic potential. However, the pathogenic role of SLPI in colorectal cancer is still unclear. Here we showed that SLPI mRNA level was significantly upregulated in colorectal cancer tissues compared to adjacent normal controls. Targeting SLPI by siRNA inhibited proliferation, migration and invasion of colorectal cancer cells lines HT29 and HT116 in vitro. Mechanistically, blockage of cancer cell growth and metastasis after SLPI knockdown was associated with down-regulation of AKT signaling. In conclusion, SLPI regulated colorectal cell growth and metastasis via AKT signaling. SLPI may be a novel biomarker and therapeutic target for colorectal cancer. Targeting AKT signaling may be effective for colorectal cancer treatment.
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Affiliation(s)
- Zhijiang Wei
- The First Department of Surgical Oncology, Cangzhou Central Hospital, Cangzhou, China
| | - Guiying Liu
- The First Department of Surgical Oncology, Cangzhou Central Hospital, Cangzhou, China
| | - Rufu Jia
- The Brain Science Unit, CangZhou Central Hospital, Cangzhou, China
| | - Wei Zhang
- The First Department of Surgical Oncology, Cangzhou Central Hospital, Cangzhou, China
| | - Li Li
- The Brain Science Unit, CangZhou Central Hospital, Cangzhou, China
| | - Yuanyuan Zhang
- The First Department of Surgical Oncology, Cangzhou Central Hospital, Cangzhou, China
| | - Zhijing Wang
- The Brain Science Unit, CangZhou Central Hospital, Cangzhou, China
| | - Xiyong Bai
- The First Department of Surgical Oncology, Cangzhou Central Hospital, Cangzhou, China
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Fattahi S, Kosari-Monfared M, Golpour M, Emami Z, Ghasemiyan M, Nouri M, Akhavan-Niaki H. LncRNAs as potential diagnostic and prognostic biomarkers in gastric cancer: A novel approach to personalized medicine. J Cell Physiol 2020; 235:3189-3206. [PMID: 31595495 DOI: 10.1002/jcp.29260] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 09/03/2019] [Indexed: 02/06/2023]
Abstract
Gastric cancer is the third leading cause of cancer death with 5-year survival rate of about 30-35%. Since early detection is associated with decreased mortality, identification of novel biomarkers for early diagnosis and proper management of patients with the best response to therapy is urgently needed. Long noncoding RNAs (lncRNAs) due to their high specificity, easy accessibility in a noninvasive manner, as well as their aberrant expression under different pathological and physiological conditions, have received a great attention as potential diagnostic, prognostic, or predictive biomarkers. They may also serve as targets for treating gastric cancer. In this review, we highlighted the role of lncRNAs as tumor suppressors or oncogenes that make them potential biomarkers for the diagnosis and prognosis of gastric cancer. Relatively, lncRNAs such as H19, HOTAIR, UCA1, PVT1, tissue differentiation-inducing nonprotein coding, and LINC00152 could be potential diagnostic and prognostic markers in patients with gastric cancer. Also, the impact of lncRNAs such as ecCEBPA, MLK7-AS1, TUG1, HOXA11-AS, GAPLINC, LEIGC, multidrug resistance-related and upregulated lncRNA, PVT1 on gastric cancer epigenetic and drug resistance as well as their potential as therapeutic targets for personalized medicine was discussed.
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Affiliation(s)
- Sadegh Fattahi
- Department of Genetics, Student Research Committee, Babol University of Medical Sciences, Babol, Iran
- Department of Genetics, Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
- Department of Biochemistry, North Research Center, Pasteur Institute, Amol, Iran
| | | | - Monireh Golpour
- Department of Immunology, Molecular and Cell Biology Research Center, Student Research Committee, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Zakieh Emami
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Ghasemiyan
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Maryam Nouri
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Haleh Akhavan-Niaki
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
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Zhang Y, Chen L, Cao Y, Chen S, Xu C, Xing J, Zhang K. LETM1 Promotes Gastric Cancer Cell Proliferation, Migration, and Invasion via the PI3K/Akt Signaling Pathway. J Gastric Cancer 2020; 20:139-151. [PMID: 32595998 PMCID: PMC7311216 DOI: 10.5230/jgc.2020.20.e12] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 03/04/2020] [Accepted: 03/06/2020] [Indexed: 12/14/2022] Open
Abstract
Purpose Globally, there is a high incidence of gastric cancer (GC). Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) is reported to play a vital role in several human malignancies. However, there is limited understanding of the role of LETM1 in GC. This study aims to investigate the effects of LETM1 on proliferation, migration, and invasion of GC cells. Materials and Methods The expression levels of LETM1 in the normal gastric mucosal epithelial cells (GES-1) and GC cells were analyzed by quantitative real-time polymerase chain reaction and western blotting. CCK-8, wound healing, and Transwell invasion assays were performed to evaluate the effect of LETM1 knockdown or overexpression on the proliferation, migration, and invasion of the GC cells, respectively. Additionally, the effect of LETM1 knockdown or overexpression on GC cell apoptosis was determined by flow cytometry. Furthermore, the effect of LETM1 knockdown or overexpression on the expression levels of PI3K/Akt signaling pathway-related proteins was evaluated by western blotting. Results The GC cells exhibited markedly higher mRNA and protein expression levels of LETM1 than the GES-1 cells. Additionally, the knockdown of LETM1 remarkably suppressed the GC cell proliferation, migration, and invasion, and promoted the apoptosis of GC cells, which were reversed upon LETM1 overexpression. Furthermore, the western blotting analysis indicated that LETM1 facilitates GC progression via the PI3K/Akt signaling pathway. Conclusions LETM1 acts as an oncogenic gene to promote GC cell proliferation, migration, and invasion via the PI3K/Akt signaling pathway. Therefore, LETM1 may be a potential target for GC diagnosis and treatment.
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Affiliation(s)
- Yunfeng Zhang
- Department of Gastroenterology, The Affiliated Provincial Hospital of Anhui Medical University, Hefei, China
| | - Lele Chen
- Department of Gastroenterology, The Affiliated Provincial Hospital of Anhui Medical University, Hefei, China
| | - Yifan Cao
- Department of Gastroenterology, The Affiliated Provincial Hospital of Anhui Medical University, Hefei, China
| | - Si Chen
- Department of Gastroenterology, The Affiliated Provincial Hospital of Anhui Medical University, Hefei, China
| | - Chao Xu
- Department of Gastroenterology, The Affiliated Provincial Hospital of Anhui Medical University, Hefei, China
| | - Jun Xing
- Department of Gastroenterology, The Affiliated Provincial Hospital of Anhui Medical University, Hefei, China
| | - Kaiguang Zhang
- Department of Gastroenterology, The Affiliated Provincial Hospital of Anhui Medical University, Hefei, China
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Ma Z, Yang J, Yang Y, Wang X, Chen G, Shi A, Lu Y, Jia S, Kang X, Lu L. Rosmarinic acid exerts an anticancer effect on osteosarcoma cells by inhibiting DJ-1 via regulation of the PTEN-PI3K-Akt signaling pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 68:153186. [PMID: 32088353 DOI: 10.1016/j.phymed.2020.153186] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 01/02/2020] [Accepted: 02/07/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Osteosarcoma is the most common type of primary malignant bone tumor. This disease has exhibited a progressively lower survival rate over the past several decades, which has resulted in it becoming a main cause of death in humans. Rosmarinic acid (RA), a water-soluble polyphenolic phytochemical, exerts powerful anticancer effects against multiple types of cancer; however, its potential effects on osteosarcoma remain unknown. Hence, the present study investigated the efficacy of RA against osteosarcoma and aimed to clarify the mechanisms underlying this process. METHODS The effects of RA on cell viability, apoptosis, cell cycle distribution, migration, invasion, and signaling molecules were analyzed by CCK-8 assay, flowcytometric analysis, wound healing assay, Transwell assay, proteomic analysis, and use of shRNAs. RESULTS RA exerted anti-proliferation and pro-apoptotic effects on U2OS and MG63 osteosarcoma cells. Apoptosis was induced via extrinsic and intrinsic pathways by increasing the Bax/Bcl-2 ratio, triggering the intracellular production of reactive oxygen species (ROS), reducing the mitochondrial membrane potential (MMP), and upregulating the cleavage rates of caspase-8, caspase-9, and caspase-3. Additionally, RA suppressed the migration and invasion of osteosarcoma cells by inhibiting the expression levels of matrix metalloproteinase-2 and -9 (MMP-2 and -9), which are associated with a weakening of the epithelial-mesenchymal transition (EMT). Moreover, proteomic analyses identified DJ-1 as a potential target for RA. Several studies have indicated an oncogenic role for DJ-1 using knockdowns via the lentiviral-mediated transfection of shRNA, which caused the conspicuous suppression of cell proliferation, migration, and invasion as well as the arrest of cell cycle progression. At the molecular level, the expression levels of DJ-1, p-PI3K, and p-Akt were reduced, whereas the protein levels of phosphatase and tensin homologue (PTEN) were increased. CONCLUSION In conjunction with the high levels of DJ-1 expression in osteosarcoma tissues and cell lines, the present results suggested that RA exhibited anticancer effects in osteosarcoma cells by inhibiting DJ-1 via regulation of the PTEN-PI3K-Akt signaling pathway. Therefore, DJ-1 might be a biological target for RA in osteosarcoma cells.
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Affiliation(s)
- Zhanjun Ma
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730000, China; Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, Gansu 730000, China
| | - Jingjing Yang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Yang Yang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Xuexi Wang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou, Gansu 730000, China; School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, China.
| | - Guohu Chen
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Ancheng Shi
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Yubao Lu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Shouning Jia
- Traditional Chinese Medicine Hospital of Qinghai Province, Xining, Qinghai 810000, China
| | - Xuewen Kang
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, Gansu 730000, China.
| | - Li Lu
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou, Gansu 730000, China; Institute of Pharmacology, School of Basic Medical Science, Lanzhou University, Lanzhou, Gansu 730000, China.
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Ruan T, Liu W, Tao K, Wu C. A Review of Research Progress in Multidrug-Resistance Mechanisms in Gastric Cancer. Onco Targets Ther 2020; 13:1797-1807. [PMID: 32184615 PMCID: PMC7053652 DOI: 10.2147/ott.s239336] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 02/15/2020] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer is one of the most common malignant tumors, and it is also one of the leading causes of cancer death worldwide. Because of its insidious symptoms and lack of early dictation screening, many cases of gastric cancer are at late stages which make it more complicated to cure. For these advanced-stage gastric cancers, combination therapy of surgery, chemotherapy, radiotherapy and target therapy would bring more benefit to the patients. However, the drug-resistance to the chemotherapy restricts its effect and might lead to treatment failure. In this review article, we discuss the mechanisms which have been found in recent years of drug resistance in gastric cancer. And we also want to find new approaches to counteract chemotherapy resistance and bring more benefits to the patients.
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Affiliation(s)
- Tuo Ruan
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Weizhen Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chuanqing Wu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Antitumor activity of ipatasertib combined with chemotherapy: results from a phase Ib study in solid tumors. Ann Oncol 2020; 31:626-633. [PMID: 32205017 DOI: 10.1016/j.annonc.2020.02.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 02/03/2020] [Accepted: 02/12/2020] [Indexed: 10/25/2022] Open
Abstract
BACKGROUND This phase Ib study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the oral AKT inhibitor ipatasertib and chemotherapy or hormonal therapy in patients with advanced or metastatic solid tumors to determine combined dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase II doses and schedules. PATIENTS AND METHODS The clinical study comprised four combination treatment arms: arm A (with docetaxel), arm B [with mFOLFOX6 (modified leucovorin, 5-fluorouracil, and oxaliplatin)], arm C (with paclitaxel), and arm D (with enzalutamide). Primary endpoints were safety and tolerability; secondary endpoints were pharmacokinetics, clinical activity per Response Evaluation Criteria in Solid Tumors v1.1, and prostate-specific antigen levels. RESULTS In total, 122 patients were enrolled. Common adverse events were diarrhea, nausea, vomiting, decreased appetite, and fatigue. The safety profiles of the combination regimens were consistent with those of the background regimens, except for diarrhea, hyperglycemia, and rash, which were previously observed with ipatasertib treatment. The only combination DLT across all treatment arms was one event of grade 3 dehydration (ipatasertib 600 mg and paclitaxel). Recommended phase II doses for ipatasertib were 600 mg (and mFOLFOX6) and 400 mg (and paclitaxel), respectively. The maximum assessed dose of ipatasertib 600 mg combined with docetaxel or enzalutamide was well tolerated. Coadministration with enzalutamide (a cytochrome P450 3A inducer) resulted in approximately 50% lower ipatasertib exposure. CONCLUSIONS Ipatasertib in combination with chemotherapy or hormonal therapy was well tolerated with a safety profile consistent with that of ATP-competitive AKT inhibitors. CLINICAL TRIAL NUMBER NCT01362374.
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Xia C, Zeng H, Zheng Y. Low‑intensity ultrasound enhances the antitumor effects of doxorubicin on hepatocellular carcinoma cells through the ROS‑miR‑21‑PTEN axis. Mol Med Rep 2020; 21:989-998. [PMID: 32016465 PMCID: PMC7003057 DOI: 10.3892/mmr.2020.10936] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 03/06/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a type of liver cancer and is a leading cause of cancer-associated mortality. In China, ~466,000 patients are diagnosed with HCC and it is responsible for ~422,000 cases of mortality each year. Surgery is the most effective treatment available; however it is only suitable for patients with early-stage HCC. Chemotherapy has been confirmed as a necessary treatment for patients with advanced HCC, although drug resistance may limit its clinical outcome. Low intensity ultrasound (LIUS) represents a novel therapeutic approach to treat patients with HCC; however, its underlying molecular mechanism remains unclear. In the present study, cell viability, apoptosis and reactive oxygen species (ROS) generation were determined via Cell Counting Kit-8, flow cytometry and 2′,7′-dichlorofluorescein diacetate assays, respectively. The expression of miRNA in HCC cells following exposure to LIUS and doxorubicin (Dox) was analyzed using a microarray and reverse transcription-quantitative polymerase chain reaction analysis. It was revealed treatment with LIUS in combination with Dox was able to induce apoptosis of Huh7 cells, increasing the intracellular levels of reactive oxygen species (ROS) and malondialdehyde. Glutathione peroxidase and superoxide dismutase 1 are ROS-scavenging enzymes, which serve important roles in the oxidative balance, preventing oxidative stress. The protein expression levels of these two enzymes were significantly decreased following treatment with LIUS combined with Dox. The present results suggested that LIUS may decrease Dox resistance in HCC cells and that LIUS may be combined with chemotherapy to treat HCC. By performing microarray analysis, the expression levels of microRNA-21 (miR-21) were decreased following treatment with LIUS combined with Dox. Functional experiments showed that knockdown of miR-21 enhanced the antitumor activity of Dox, whereas overexpression of miR-21 reversed these effects. Phosphatase and tensin homolog (PTEN), a well-known tumor suppressor, was revealed to be a direct target of miR-21, and its translation was suppressed by miR-21. Finally, it was determined that combined treatment of LIUS and Dox induced anticancer effects by blocking the activation of the AKT/mTOR pathway, as demonstrated by the downregulation of phosphorylated (p-)AKT and p-mTOR; N-acetylcysteine, a general ROS inhibitor reversed the suppressive effects on the AKT/mTOR pathway mediated by LIUS and Dox. Collectively, the present results suggested that LIUS increased cell sensitivity to Dox via the ROS/miR-21/PTEN pathway. Chemotherapy combined with LIUS may represent a novel effective therapeutic strategy to treat patients with advanced HCC.
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Affiliation(s)
- Chunhua Xia
- Department of Ultrasound, Suqian Obstetrics and Gynecology Hospital, Suqian, Jiangsu 223800, P.R. China
| | - Huabei Zeng
- Department of Ultrasound, Suqian Obstetrics and Gynecology Hospital, Suqian, Jiangsu 223800, P.R. China
| | - Yanfen Zheng
- Department of Ultrasound, School of Imaging of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia 014060, P.R. China
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Cai J, Cai H, Chen J, Yang X. Identifying "Many-to-Many" Relationships between Gene-Expression Data and Drug-Response Data via Sparse Binary Matching. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2020; 17:165-176. [PMID: 29994482 DOI: 10.1109/tcbb.2018.2849708] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Identifying gene-drug patterns is a critical step in pharmacology for unveiling disease mechanisms and drug discovery. The availability of high-throughput technologies accumulates massive large-scale pharmacological and genomic data, and thus provides a new substantial opportunity to deeply understand how the oncogenic genes and the therapeutic drugs relate to each other. However, most previous studies merely used the pharmacological and genomic datasets without any prior knowledge to infer the gene-drug patterns. Here, we proposed a novel network-guided sparse binary matching model (NSBM) to decode these relationships hidden in the datasets. Not only the large-scale gene-expression data and drug-response data are jointly analyzed in our method, but also the additional prior information of genes and drugs are integrated into the form of network-based regularization. The essential structure of the NSBM model is a convex quadratic minimization problem with network-based penalties. It was demonstrated to be superior when compared with two benchmark methods through extensive experiments on both synthetic and empirical data. Posterior validation, including gene-ontology and enrichment analysis, confirmed the effectiveness of NSBM in revealing gene-drug patterns on a large-scale heterogeneous data source.
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Son ES, Kim SH, Kim YO, Lee YE, Kyung SY, Jeong SH, Kim YJ, Park JW. Coix lacryma-jobi var. ma-yuen Stapf sprout extract induces cell cycle arrest and apoptosis in human cervical carcinoma cells. Altern Ther Health Med 2019; 19:312. [PMID: 31729992 PMCID: PMC6858790 DOI: 10.1186/s12906-019-2725-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Accepted: 10/23/2019] [Indexed: 12/13/2022]
Abstract
Background Cervical cancer is the second-leading cause of cancer-related mortality in females. Coix lacryma-jobi L. var. ma-yuen (Rom.Caill.) Stapf ex Hook. f. is the most widely recognized medicinal herb for its remedial effects against inflammation, endocrine system dysfunctions, warts, chapped skin, rheumatism, and neuralgia and is also a nourishing food. Methods To investigate the activity of Coix lacryma-jobi sprout extract (CLSE) on cell proliferation in human cervical cancer HeLa cells, we conducted a Cell Counting Kit-8 (CCK-8) assay. Flow-cytometric analysis and western blot analysis were performed to verify the effect of CLSE on the regulation of the cell cycle and apoptosis in HeLa cells. Results We observed that CLSE significantly inhibited cell proliferation. Furthermore, CLSE dose-dependently promoted cell cycle arrest at the sub-G1/ S phase in HeLa cells, as detected by bromodeoxyuridine (BrdU) staining. The cell-cycle-arrest effects of CLSE in HeLa cells were associated with downregulation of cyclin D1 and cyclin-dependent kinases (CDKs) 2, 4, and 6. Moreover, CLSE induced apoptosis, as determined by flow-cytometric analysis and nuclear DNA fragmentation with Annexin V/propidium iodide (PI) and 4′6′-diamidino-2-phenylindole (DAPI) staining. Induction of apoptosis by CLSE was involved in inhibition of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) and upregulation of the apoptotic proteins p53, cleaved poly (ADP-ribose) polymerase (PARP), cleaved caspase-3, and cleaved caspase-8. Finally, we observed that CLSE inactivated the phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) pathways. Conclusions CLSE causes cell cycle arrest and apoptotic cell death through inactivation of the PI3K/AKT pathway in HeLa cells, suggesting it is a viable therapeutic agent for cervical cancer owing to its anticancer effects.
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Huang X, Li Z, Zhang Q, Wang W, Li B, Wang L, Xu Z, Zeng A, Zhang X, Zhang X, He Z, Li Q, Sun G, Wang S, Li Q, Wang L, Zhang L, Xu H, Xu Z. Circular RNA AKT3 upregulates PIK3R1 to enhance cisplatin resistance in gastric cancer via miR-198 suppression. Mol Cancer 2019; 18:71. [PMID: 30927924 PMCID: PMC6441201 DOI: 10.1186/s12943-019-0969-3] [Citation(s) in RCA: 308] [Impact Index Per Article: 51.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 02/21/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Cisplatin (CDDP) treatment is one of the most predominant chemotherapeutic strategies for patients with gastric cancer (GC). A better understanding of the mechanisms of CDDP resistance can greatly improve therapeutic efficacy in patients with GC. Circular RNAs (circRNAs) are a class of noncoding RNAs whose functions are related to the pathogenesis of cancer, but, in CDDP resistance of GC remains unknown. METHODS circAKT3 (hsa_circ_0000199, a circRNA originating from exons 8, 9, 10, and 11 of the AKT3 gene) was identified by RNA sequencing and verified by quantitative reverse transcription PCR. The role of circAKT3 in CDDP resistance in GC was assessed both in vitro and in vivo. Luciferase reporter assay, biotin-coupled RNA pull-down and fluorescence in situ hybridization (FISH) were conducted to evaluate the interaction between circAKT3 and miR-198. Functional experiments were measured by western blotting, a cytotoxicity assay, clonogenic assay and flow cytometry. RESULTS The expression of circAKT3 was higher in CDDP-resistant GC tissues and cells than in CDDP-sensitive samples. The upregulation of circAKT3 in GC patients receiving CDDP therapy was significantly associated with aggressive characteristics and was an independent risk factor for disease-free survival (DFS). Our data indicated that circAKT3 promotes DNA damage repair and inhibits the apoptosis of GC cells in vivo and in vitro. Mechanistically, we verified that circAKT3 could promote PIK3R1 expression by sponging miR-198. CONCLUSIONS circAKT3 plays an important role in the resistance of GC to CDDP. Thus, our results highlight the potential of circAKT3 as a therapeutic target for GC patients receiving CDDP therapy.
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Affiliation(s)
- Xiaoxu Huang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China
- Department of Gastrointestinal Surgery, The First Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Zheng Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China
| | - Qiang Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China
| | - Weizhi Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China
| | - Bowen Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China
| | - Lu Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China
| | - Zhipeng Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China
| | - Ailiang Zeng
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xing Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China
| | - Xuan Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China
| | - Zhongyuan He
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China
| | - Qiang Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China
| | - Guangli Sun
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China
| | - Sen Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China
| | - Qing Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China
| | - Linjun Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China
| | - Lu Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China
| | - Hao Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu province, China.
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Ding H, Sun J, Li R, Wang G. Retracted Article: Long non-coding RNA GACAT1 alleviates doxorubicin and vincristine resistance through a PTEN/AKT/mTOR/S6K1 regulatory pathway in gastric cancer. RSC Adv 2019; 9:8048-8055. [PMID: 35521206 PMCID: PMC9061239 DOI: 10.1039/c8ra10030f] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 02/22/2019] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is a major global health problem. Chemotherapy is a common therapeutic strategy for cancers including GC. However, chemoresistance strikingly limits the clinical applications of chemotherapeutic drugs. Long non-coding RNAs (lncRNAs) have been widely reported to be implicated in the pathogenesis and chemoresistance of cancers including GC. Our work aims to investigate the roles and molecular mechanisms of lncRNA gastric cancer-associated transcript 1 (GACAT1) in regulating doxorubicin (ADR) and vincristine (VCR) resistance in GC. In this text, RT-qPCR assay showed that GACAT1 expression was markedly reduced in ADR- or VCR-resistant GC (SGC7901/ADR or SGC7901/VCR) cells and GC tissues. CCK-8 assay and flow cytometry analysis revealed that GACAT1 overexpression alleviated the resistance of GC cells to ADR and VCR. RT-qPCR and western blot assay disclosed that GACAT1 deactivated the AKT/mTOR/S6K1 signaling pathway and promoted PTEN expression in SGC7901/ADR or SGC7901/VCR cells. Restoration experiments demonstrated that GACAT1 attenuated ADR or VCR resistance by regulating the PTEN/AKT/mTOR/S6K1 pathway in SGC7901/ADR or SGC7901/VCR cells. In vivo experiments demonstrated that GACAT1 overexpression inhibited tumor growth and enhanced ADR- or VCR-mediated anti-tumor effects in GC xenograft tumor models. Taken together, these data revealed that GACAT1 weakened the resistance of GC cells to ADR and VCR by the PTEN/AKT/mTOR/S6K1 regulatory pathway in vitro and in vivo, shedding new light on GACAT1 upregulation as a potential strategy to alleviate chemoresistance in GC.
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Affiliation(s)
- Hengxuan Ding
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University Jianshe Road 1 Zhengzhou 450052 P. R. China +86-0371-67967137
| | - Junfeng Sun
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University Jianshe Road 1 Zhengzhou 450052 P. R. China +86-0371-67967137
| | - Ruixin Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University Jianshe Road 1 Zhengzhou 450052 P. R. China +86-0371-67967137
| | - Guojun Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University Jianshe Road 1 Zhengzhou 450052 P. R. China +86-0371-67967137
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Fu XH, Chen ZT, Wang WH, Fan XJ, Huang Y, Wu XB, Huang JL, Wang JX, Lin HJ, Tan XL, Wang L, Wang JP. KRAS G12V Mutation is an Adverse Prognostic Factor of Chinese Gastric Cancer Patients. J Cancer 2019; 10:821-828. [PMID: 30854087 PMCID: PMC6400811 DOI: 10.7150/jca.27899] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 12/14/2018] [Indexed: 12/13/2022] Open
Abstract
This study aims to investigate the molecular characteristics of Chinese gastric cancer patients. In our study, the KRAS, BRAF, and PIK3CA mutation status of 485 GC patients were analyzed by Sanger sequencing. Kaplan-Meier analysis was used to plot survival curves according to different genotypes. The results show that the frequency of KRAS, BRAF and PIK3CA mutations were 4.1%, 1.2% and 3.5%, respectively. BRAF mutations were significantly concentrated in stage III and IV gastric cancer (P=0.009). KRAS G12V mutation carriers have much shorter OS than other mutation carriers and wild-type group patients (P=0.013). In conclusion, only the KRAS G12V mutation has an adverse effect on patient survival.
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Affiliation(s)
- Xin-Hui Fu
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China.,Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China
| | - Zhi-Ting Chen
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China.,Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China
| | - Wen-Hui Wang
- Department of Information and Technology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China
| | - Xin-Juan Fan
- Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China
| | - Yan Huang
- Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China
| | - Xiao-Bin Wu
- Department of GI Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China
| | - Jing-Lin Huang
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China.,Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China
| | - Jing-Xuan Wang
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China.,Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China
| | - Han-Jie Lin
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China.,Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China
| | - Xiao-Li Tan
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China.,Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China
| | - Lei Wang
- Department of GI Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China
| | - Jian-Ping Wang
- Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, China
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Han T, Wu N, Wang Y, Shen W, Zou J. miR‑16‑2‑3p inhibits cell proliferation and migration and induces apoptosis by targeting PDPK1 in maxillary primordium mesenchymal cells. Int J Mol Med 2019; 43:1441-1451. [PMID: 30664182 PMCID: PMC6365086 DOI: 10.3892/ijmm.2019.4070] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 01/16/2019] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) post-transcriptionally regulate gene expression by targeting the 3′ untranslated region (UTR) of target genes, and serve diverse roles in cell proliferation, differentiation and apoptosis. However, the association between miR-16-2-3p and 3-phosphoinositide-dependent protein kinase-1 (PDPK1) in nonsyndromic cleft lip (NSCL) remains unclear. In the present study, a luciferase activity assay indicated that miR-16-2-3p negatively regulated PDPK1 in maxillary primordium mesenchymal cells (MPMCs). In addition, it was confirmed that the expression levels of miR-16-2-3p was markedly increased in cleft lip tissues compared with those in adjacent normal lip tissues. A negative correlation between miR-16-2-3p and PDPK1 in cleft lip tissues was observed. Furthermore, miR-16-2-3p inhibited cell proliferation and migration, and induced apoptosis of MPMCs via repressing PDPK1. Finally, miR-16-2-3p exerted its suppressive role in MPMCs by inhibiting the PDPK1/protein kinase B signaling pathway. These results indicate that miR-16-2-3p may inhibit cell proliferation and migration, and promote apoptosis in MPMCs through repression of PDPK1 and may be a potential target for future clinical prevention and treatment of NSCL.
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Affiliation(s)
- Tao Han
- Department of Burns and Plastic Surgery, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| | - Ni Wu
- Department of Burns and Plastic Surgery, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| | - Youjing Wang
- Department of Burns and Plastic Surgery, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| | - Weimin Shen
- Department of Burns and Plastic Surgery, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| | - Jijun Zou
- Department of Burns and Plastic Surgery, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
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Price ZK, Lokman NA, Ricciardelli C. Differing Roles of Hyaluronan Molecular Weight on Cancer Cell Behavior and Chemotherapy Resistance. Cancers (Basel) 2018; 10:E482. [PMID: 30513961 PMCID: PMC6316154 DOI: 10.3390/cancers10120482] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 11/28/2018] [Accepted: 11/29/2018] [Indexed: 02/07/2023] Open
Abstract
Hyaluronan (HA), a glycosaminoglycan located in the extracellular matrix, is important in embryo development, inflammation, wound healing and cancer. There is an extensive body of research demonstrating the role of HA in all stages of cancer, from initiation to relapse and therapy resistance. HA interacts with multiple cell surface receptors, including CD44, receptor for hyaluronan mediated motility (RHAMM) and intracellular signaling pathways, including receptor tyrosine kinase pathways, to promote the survival and proliferation of cancer cells. Additionally, HA promotes the formation of cancer stem cell (CSC) populations, which are hypothesized to be responsible for the initiation of tumors and therapy resistance. Recent studies have identified that the molecular weight of HA plays differing roles on both normal and cancer cell behavior. This review explores the role of HA in cancer progression and therapy resistance and how its molecular weight is important in regulating CSC populations, epithelial to mesenchymal transition (EMT), ATP binding cassette (ABC) transporter expression and receptor tyrosine kinase pathways.
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Affiliation(s)
- Zoe K Price
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, South Australia 5000, Australia.
| | - Noor A Lokman
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, South Australia 5000, Australia.
| | - Carmela Ricciardelli
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, South Australia 5000, Australia.
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Bashash D, Delshad M, Riyahi N, Safaroghli-Azar A, Pourbagheri-Sigaroodi A, Momeny M. Inhibition of PI3K signaling pathway enhances the chemosensitivity of APL cells to ATO: Proposing novel therapeutic potential for BKM120. Eur J Pharmacol 2018; 841:10-18. [DOI: 10.1016/j.ejphar.2018.10.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 10/01/2018] [Accepted: 10/10/2018] [Indexed: 01/25/2023]
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Nobiletin Enhances Chemosensitivity to Adriamycin through Modulation of the Akt/GSK3β/β⁻Catenin/MYCN/MRP1 Signaling Pathway in A549 Human Non-Small-Cell Lung Cancer Cells. Nutrients 2018; 10:nu10121829. [PMID: 30486290 PMCID: PMC6316077 DOI: 10.3390/nu10121829] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 11/21/2018] [Accepted: 11/22/2018] [Indexed: 01/09/2023] Open
Abstract
Drug resistance is a major problem in the treatment of non-small-cell lung cancer (NSCLC). In this study, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed to identify the differentially expressed genes in Adriamycin (ADR)-resistant NSCLC A549/ADR cells compared with parental A549 cells. Among the tested phytochemicals, nobiletin (NBT) is able to overcome the ADR resistance of A549/ADR cells. NBT treatment decreased the expression of a neuroblastoma-derived MYC (MYCN) and multidrug resistance-associated protein 1 (MRP1) as well as downregulating Akt, GSK3β, and β-catenin. Consistent with these results, NBT treatment resulted in the accumulation of intracellular ADR. A combination index (CI) assay confirmed the synergistic effect of combined treatment with NBT and ADR in reducing the viability of A549/ADR cells (CI = 0.152). Combined treatment with NBT and ADR enhanced apoptosis in A549/ADR cells, as evidenced by increased caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage, and sub-G1 population compared to treatment with ADR alone. In vivo experiments using a mouse xenograft model revealed that combination therapy with NBT and ADR significantly reduced tumor volume by 84.15%. These data suggest that NBT can sensitize ADR-induced cytotoxicity against A549/ADR cells by inhibiting MRP1 expression, indicating that NBT could serve as an effective adjuvant agent for ADR-based chemotherapy in lung cancer.
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