Role of Fasting Mimicking Diet in Farnesoid x Receptor for Suppressing Epithelial-to-Mesenchymal Transition, Cell Cycle Progression, and Viability of Prostate Cancer Cells
Keywords:Keywords: FXR; FMD; epithelial-mesenchymal transition; cell cycle; migration; invasion.
The systemic and resistant nature of metastatic castration-resistant prostate cancers (mCRPC) renders it largely incurable even after intensive multimodal therapy. Proliferation, survival, and epithelial-mesenchymal transition (EMT) are three fundamental events that are deeply linked to carcinogenesis. Hence, it is necessary to find a new combination of several therapies, targeting those vital mechanisms without causing side effects. Significant research works have shown differential low expression of the metabolic Farnesoid X receptor (FXR) in primary and metastatic prostate cancer suggesting their importance in prostate pathogenesis. Obticholic acid (INT 747), a potent FXR agonist is widely used in primary biliary cholangitis, and Fasting mimicking Diet (FMD) both were drastically showed effects on different cancer progression. We hypothesized that FXR and FMD may inhibit proliferation and the metastatic phenotype in PC-3 prostate cancer cells. Analyses of the cell viability, cell cycle, migration, and matrigel invasion assays were performed to elucidate how INT 747 and /or FMD functions in prostate cancer. In this study, INT 747 treatment caused apoptotic morphological changes and significantly reduced the survival of PC-3 cells incubated in normal mediums. Furthermore, we showed that the combination of the INT 747 and FMD was much more harmful to cancer cells than the treatment with INT 747 or FMD alone. Moreover, our study showed that INT 747 either alone or combined with FMD robustly induced cell cycle arrest at the S phase. Interestingly, the combination treatment on PC-3 cells not only showed several lines of evidence of apoptotic cells death but also inhibited carcinogenic potential as evaluated by impairment of spheroid formation capacity and delayed wound healing and matrigel invasion. At the cellular level, FXR activation resulted in down-regulation of procaspase -3, vimentin, and MMP9, which triggers apoptotic cell death, cell cycle arrest, and switch from mesenchymal to an epithelial phenotype. Collectively, FXR activation alone markedly decreases, and when combined with FMD abrogates the survival and carcinogenic potential of metastatic prostate cancer cells.
Kimura T, Egawa S. Epidemiology of prostate cancer in Asian countries. International Journal of Urology. 2018;25(6):524-31.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. 2021;71(3):209-49.
Westhofen T, Chaloupka M, Herlemann A, Todenhöfer T, Stief CG, Kretschmer A. [Advanced prostate cancer - modern therapies, better prognosis?]. MMW Fortschr Med. 2021;163(7):41-3.
Rycaj K, Li H, Zhou J, Chen X, Tang DG. Cellular determinants and microenvironmental regulation of prostate cancer metastasis. Semin Cancer Biol. 2017;44:83-97.
Gourdin T. Recent progress in treating advanced prostate cancer. Curr Opin Oncol. 2020;32(3):210-5.
Guccini I, Revandkar A, D'Ambrosio M, Colucci M, Pasquini E, Mosole S, et al. Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis. Cancer Cell. 2021;39(1):68-82.e9.
Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nature Reviews Molecular Cell Biology. 2014;15(3):178-96.
Han CY. Update on FXR Biology: Promising Therapeutic Target? Int J Mol Sci. 2018;19(7).
Zhang Y, LaCerte C, Kansra S, Jackson JP, Brouwer KR, Edwards JE. Comparative potency of obeticholic acid and natural bile acids on FXR in hepatic and intestinal in vitro cell models. Pharmacol Res Perspect. 2017;5(6).
Di Matteo S, Nevi L, Costantini D, Overi D, Carpino G, Safarikia S, et al. The FXR agonist obeticholic acid inhibits the cancerogenic potential of human cholangiocarcinoma. PLOS ONE. 2019;14(1):e0210077.
Yu J, Yang K, Zheng J, Zhao W, Sun X. Synergistic tumor inhibition of colon cancer cells by nitazoxanide and obeticholic acid, a farnesoid X receptor ligand. Cancer Gene Ther. 2021;28(6):590-601.
Sun L, Cai J, Gonzalez FJ. The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer. Nat Rev Gastroenterol Hepatol. 2021;18(5):335-47.
Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab. 2014;19(2):181-92.
Pascual-Geler M, Urquiza-Salvat N, Cozar JM, Robles-Fernandez I, Rivas A, Martinez-Gonzalez LJ, et al. The influence of nutritional factors on prostate cancer incidence and aggressiveness. Aging Male. 2018;21(1):31-9.
Barnes KA, Ball LE, Galvão DA, Newton RU, Chambers SK. Nutrition care guidelines for men with prostate cancer undergoing androgen deprivation therapy: do we have enough evidence? Prostate Cancer Prostatic Dis. 2019;22(2):221-34.
Wang L, Yu Z, Ren S, Song J, Wang J, Du G. Metabolic reprogramming in colon cancer reversed by DHTS through regulating PTEN/AKT/HIF1alpha mediated signal pathway. Biochim Biophys Acta Gen Subj. 2018;1862(10):2281-92.
Zi X, Guo Y, Simoneau AR, Hope C, Xie J, Holcombe RF, et al. Expression of Frzb/secreted Frizzled-related protein 3, a secreted Wnt antagonist, in human androgen-independent prostate cancer PC-3 cells suppresses tumor growth and cellular invasiveness. Cancer Res. 2005;65(21):9762-70.
Kumar P, Nagarajan A, Uchil PD. Analysis of Cell Viability by the MTT Assay. Cold Spring Harb Protoc. 2018;2018(6).
Liang C-C, Park AY, Guan J-L. In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nature Protocols. 2007;2(2):329-33.
Chen Q-Y, Wang G-G, Li W, Jiang Y-X, Lu X-H, Zhou P-P. Heme Oxygenase-1 Promotes Delayed Wound Healing in Diabetic Rats. J Diabetes Res. 2016;2016:9726503-.
Wang L, Liu Y, Zhou Y, Wang J, Tu L, Sun Z, et al. Zoledronic acid inhibits the growth of cancer stem cell derived from cervical cancer cell by attenuating their stemness phenotype and inducing apoptosis and cell cycle arrest through the Erk1/2 and Akt pathways. Journal of Experimental & Clinical Cancer Research. 2019;38(1).
Burleson KM, Hansen LK, Skubitz AP. Ovarian carcinoma spheroids disaggregate on type I collagen and invade live human mesothelial cell monolayers. Clin Exp Metastasis. 2004;21(8):685-97.
Teo MY, Rathkopf DE, Kantoff P. Treatment of Advanced Prostate Cancer. Annu Rev Med. 2019;70:479-99.
Al-Khfajy WSD. Role Of Transmembrane 141 in Cholesterol Metabolism: Kent State University; 2014.
Al-khfajy, Wrood S; Kathem, Sarmed H; Aboddy, Amani Anees; Hatem, Suhad Faisal; Zalzala, Munaf H; et al. Farnesoid X Receptor is an Exciting New Perspective Target For Treatment Of Diverse Pathological Disorders: Review .Journal of Pharmaceutical Sciences and Research; Vol. 10, Iss. 9, (Sep 2018): 2292-2296.
Nafeer, S.A., Zalzala, M.H. Possible amelioration of the severity of nutritional steatohepatitis by guggulsterone in mice Iraqi Journal of Pharmaceutical Sciences, 2019, 28(1).
Girisa S, Henamayee S, Parama D, Rana V, Dutta U, Kunnumakkara AB. Targeting Farnesoid X receptor (FXR) for developing novel therapeutics against cancer. Mol Biomed. 2021;2(1):21-.
Lv B, Ma L, Tang W, Huang P, Yang B, Wang L, et al. FXR Acts as a Metastasis Suppressor in Intrahepatic Cholangiocarcinoma by Inhibiting IL-6-Induced Epithelial-Mesenchymal Transition. Cellular Physiology and Biochemistry. 2018;48(1):158-72.
Li S, Xu Z, Guo J, Zheng J, Sun X, Yu J. Farnesoid X receptor activation induces antitumour activity in colorectal cancer by suppressing JAK2/STAT3 signalling via transactivation of SOCS3 gene. J Cell Mol Med. 2020;24(24):14549-60.
Green BJ, Nguyen V, Atenafu E, Weeber P, Duong BTV, Thiagalingam P, et al. Phenotypic Profiling of Circulating Tumor Cells in Metastatic Prostate Cancer Patients Using Nanoparticle-Mediated Ranking. Analytical Chemistry. 2019;91(15):9348-55.
Bae H, Go YH, Kwon T, Sung BJ, Cha HJ. A Theoretical Model for the Cell Cycle and Drug Induced Cell Cycle Arrest of FUCCI Systems with Cell-to-Cell Variation during Mitosis. Pharm Res. 2019;36(4):57.
Anno Y, Kubo T, Ueki R, Yano M, Sasaki K, Ohba H, et al. Synthesis of DNA conjugates by solid phase fragment condensation. Nucleosides Nucleotides Nucleic Acids. 2003;22(5-8):1451-3.
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