Knockdown of PGM1 enhances anticancer effects of orlistat in gastric cancer under glucose deprivation
Tóm tắt
Phosphoglucomutase 1 (PGM1) acts as an important regulator in glucose metabolism. However, the role of PGM1 in gastric cancer (GC) remains unclear. This study aims to investigate the role of PGM1 and develop novel regimens based on metabolic reprogramming in GC. Correlation and enrichment analyses of PGM1 were conducted based on The Cancer Genome Atlas database. Data derived from the Kaplan–Meier Plotter database were analyzed to evaluate correlations between PGM1 expression and survival time of GC patients. Cell counting kit-8, 5-Ethynyl-2-deoxyuridine, flow cytometry assays, generation of subcutaneous tumor and lung metastasis mouse models were used to determine growth and metastasis in vitro and in vivo. Cell glycolysis was detected by a battery of glycolytic indicators, including lactate, pyruvic acid, ATP production and glucose uptake. Fatty Acid Synthase (FASN) activity and expression levels of lipid enzymes were determined to reflect on lipid metabolism. Correlation and enrichment analyses suggested that PGM1 was closely associated with cell viability, proliferation and metabolism. PGM1 was overexpressed in GC tissues and cell lines. High PGM1 expression served as an indicator of shorter survival for specific subpopulation of GC patients. It was also correlated with pathological tumor stage and pathological tumor node metastasis stage of GC. Under the glucose deprivation condition, knockdown of PGM1 significantly suppressed cell viability, proliferation and glycolysis, whereas lipid metabolism was enhanced. Orlistat, as a drug that was designed to inhibit FASN activity, effectively induced apoptosis and suppressed lipid metabolism in GC. However, orlistat conversely increased glycolytic levels. Orlistat exhibited more significant inhibitive effects on GC progression after knockdown of PGM1 under glucose deprivation due to combination of glycolysis and lipid metabolism both in vitro and in vivo. Downregulation of PGM1 expression under glucose deprivation enhanced anti-cancer effects of orlistat. This combination application may serve as a novel strategy for GC treatment.
Tài liệu tham khảo
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.
Boroughs LK, DeBerardinis RJ. Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol. 2015;17(4):351–9.
Ganapathy-Kanniappan S. Molecular intricacies of aerobic glycolysis in cancer: current insights into the classic metabolic phenotype. Crit Rev Biochem Mol Biol. 2018;53(6):667–82.
Zhang Y, Shi J, Liu X, Xiao Z, Lei G, Lee H, Koppula P, Cheng W, Mao C, Zhuang L, et al. H2A monoubiquitination links glucose availability to epigenetic regulation of the endoplasmic reticulum stress response and cancer cell death. Cancer Res. 2020;80(11):2243–56.
Mitsuzuka K, Kyan A, Sato T, Orikasa K, Miyazato M, Aoki H, Kakoi N, Narita S, Koie T, Namima T, et al. Influence of 1 year of androgen deprivation therapy on lipid and glucose metabolism and fat accumulation in Japanese patients with prostate cancer. Prostate Cancer Prostatic Dis. 2016;19(1):57–62.
Czumaj A, Zabielska J, Pakiet A, Mika A, Rostkowska O, Makarewicz W, Kobiela J, Sledzinski T, Stelmanska E. In vivo effectiveness of orlistat in the suppression of human colorectal cancer cell proliferation. Anticancer Res. 2019;39(7):3815–22.
Peng H, Wang Q, Qi X, Wang X, Zhao X. Orlistat induces apoptosis and protective autophagy in ovarian cancer cells: involvement of Akt-mTOR-mediated signaling pathway. Arch Gynecol Obstet. 2018;298(3):597–605.
Zhou X, Chang TL, Chen S, Liu T, Wang H, Liang JF. Polydopamine-decorated orlistat-loaded hollow capsules with an enhanced cytotoxicity against cancer cell lines. Mol Pharm. 2019;16(6):2511–21.
Li Y, Liang R, Sun M, Li Z, Sheng H, Wang J, Xu P, Liu S, Yang W, Lu B, et al. AMPK-dependent phosphorylation of HDAC8 triggers PGM1 expression to promote lung cancer cell survival under glucose starvation. Cancer Lett. 2020;478:82–92.
Curtis M, Kenny HA, Ashcroft B, Mukherjee A, Johnson A, Zhang Y, Helou Y, Batlle R, Liu X, Gutierrez N, et al. Fibroblasts mobilize tumor cell glycogen to promote proliferation and metastasis. Cell Metab. 2019;29(1):141-155.e149.
Elgendy M, Cirò M, Hosseini A, Weiszmann J, Mazzarella L, Ferrari E, Cazzoli R, Curigliano G, DeCensi A, Bonanni B, et al. Combination of hypoglycemia and metformin impairs tumor metabolic plasticity and growth by modulating the PP2A-GSK3β-MCL-1 axis. Cancer Cell. 2019;35(5):798-815.e795.
Gao Y, Cai A, Xi H, Li J, Xu W, Zhang Y, Zhang K, Cui J, Wu X, Wei B, et al. Ring finger protein 43 associates with gastric cancer progression and attenuates the stemness of gastric cancer stem-like cells via the Wnt-β/catenin signaling pathway. Stem Cell Res Ther. 2017;8(1):98.
Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23(1):27–47.
Zhang H, Deng T, Liu R, Ning T, Yang H, Liu D, Zhang Q, Lin D, Ge S, Bai M, et al. CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer. Mol Cancer. 2020;19(1):43.
Gan L, Meng J, Xu M, Liu M, Qi Y, Tan C, Wang Y, Zhang P, Weng W, Sheng W, et al. Extracellular matrix protein 1 promotes cell metastasis and glucose metabolism by inducing integrin β4/FAK/SOX2/HIF-1α signaling pathway in gastric cancer. Oncogene. 2018;37(6):744–55.
Li L, Liang Y, Kang L, Liu Y, Gao S, Chen S, Li Y, You W, Dong Q, Hong T, et al. Transcriptional regulation of the Warburg effect in cancer by SIX1. Cancer Cell. 2018;33(3):368-385.e367.
Chen J, Yu Y, Li H, Hu Q, Chen X, He Y, Xue C, Ren F, Ren Z, Li J, et al. Long non-coding RNA PVT1 promotes tumor progression by regulating the miR-143/HK2 axis in gallbladder cancer. Mol Cancer. 2019;18(1):33.
Pereira PMR, Mandleywala K, Ragupathi A, Lewis JS. Acute statin treatment improves antibody accumulation in EGFR- and PSMA-expressing tumors. Clin Cancer Res. 2020;26(23):6215–29.
Chen MC, Hsu LL, Wang SF, Hsu CY, Lee HC, Tseng LM. ROS mediate xCT-dependent cell death in human breast cancer cells under glucose deprivation. Cells. 2020;9(7):1598.
Zhang M, Liu T, Sun H, Weng W, Zhang Q, Liu C, Han Y, Sheng W. Pim1 supports human colorectal cancer growth during glucose deprivation by enhancing the Warburg effect. Cancer Sci. 2018;109(5):1468–79.
Whitehouse DB, Tomkins J, Lovegrove JU, Hopkinson DA, McMillan WO. A phylogenetic approach to the identification of phosphoglucomutase genes. Mol Biol Evol. 1998;15(4):456–62.
Preisler N, Cohen J, Vissing CR, Madsen KL, Heinicke K, Sharp LJ, Phillips L, Romain N, Park SY, Newby M, et al. Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency. Mol Genet Metab. 2017;122(3):117–21.
Jin GZ, Zhang Y, Cong WM, Wu X, Wang X, Wu S, Wang S, Zhou W, Yuan S, Gao H, et al. Phosphoglucomutase 1 inhibits hepatocellular carcinoma progression by regulating glucose trafficking. PLoS Biol. 2018;16(10):e2006483.
Nagy Á, Munkácsy G, Győrffy B. Pancancer survival analysis of cancer hallmark genes. Sci Rep. 2021;11(1):6047.
Chuang HY, Lee YP, Lin WC, Lin YH, Hwang JJ. Fatty acid inhibition sensitizes androgen-dependent and -independent prostate cancer to radiotherapy via FASN/NF-κB pathway. Sci Rep. 2019;9(1):13284.
de Almeida LY, Mariano FS, Bastos DC, Cavassani KA, Raphelson J, Mariano VS, Agostini M, Moreira FS, Coletta RD, Mattos-Graner RO, et al. The antimetastatic activity of orlistat is accompanied by an antitumoral immune response in mouse melanoma. Cancer Chemother Pharmacol. 2020;85(2):321–30.
Kim BS, Chung TW, Choi HJ, Bae SJ, Cho HR, Lee SO, Choi JH, Joo JK, Ha KT. Caesalpinia sappan induces apoptotic cell death in ectopic endometrial 12Z cells through suppressing pyruvate dehydrogenase kinase 1 expression. Exp Ther Med. 2021;21(4):357.
Sun LT, Zhang LY, Shan FY, Shen MH, Ruan SM. Jiedu Sangen decoction inhibits chemoresistance to 5-fluorouracil of colorectal cancer cells by suppressing glycolysis via PI3K/AKT/HIF-1α signaling pathway. Chin J Nat Med. 2021;19(2):143–52.
Mukhopadhyay S, Vander Heiden MG, McCormick F. The metabolic landscape of RAS-driven cancers from biology to therapy. Nature cancer. 2021;2(3):271–83.
Mukhopadhyay S, Goswami D, Adiseshaiah PP, Burgan W, Yi M, Guerin TM, Kozlov SV, Nissley DV, McCormick F. Undermining glutaminolysis bolsters chemotherapy while NRF2 promotes chemoresistance in KRAS-driven pancreatic cancers. Cancer Res. 2020;80(8):1630–43.
Hewitt LC, Saito Y, Wang T, Matsuda Y, Oosting J, Silva ANS, Slaney HL, Melotte V, Hutchins G, Tan P, et al. KRAS status is related to histological phenotype in gastric cancer: results from a large multicentre study. Gastric Cancer. 2019;22(6):1193–203.
Liu M, Yao B, Gui T, Guo C, Wu X, Li J, Ma L, Deng Y, Xu P, Wang Y, et al. PRMT5-dependent transcriptional repression of c-Myc target genes promotes gastric cancer progression. Theranostics. 2020;10(10):4437–52.