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Protein Phosphatase 2a Inhibits Gastric Cancer Cell Glycolysis by Reducing MYC Signaling

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Abstract

Aerobic glycolysis, also known as the Warburg effect, has emerged as a hallmark of cancer and is associated with tumor progression and unfavorable clinical outcomes in cancer patients. PP2A is a highly conserved eukaryotic serine/threonine protein phosphatase that functions as a tumor suppressor in a variety of human cancers. However, the relationship between PP2A and the Warburg effect in gastric cancer has yet to be fully understood. In this study, the expression profile of two endogenous inhibitors of PP2A, SET and CIP2A, in gastric cancer, were analyzed by real-time quantitative polymerase chain reaction. Loss-of-function and gain-of-function studies were performed to investigate the roles of PP2A in gastric cancer cell proliferation and glycolysis. Cell biological, molecular, and biochemical approaches were employed to uncover the underlying mechanisms. The results showed that SET and CIP2A were overexpressed in gastric cancer and associated with a decreased PP2A activity. Pharmacological activation of PP2A with FTY-720 and DT-061 in two gastric cancer cell lines significantly reduced gastric cancer cell proliferation and glycolytic ability. Importantly, inhibition of PP2A activity by genetic silencing of PPP2R5A resulted in a growth advantage, which can be largely compromised by the addition of the glycolysis inhibitor 2-Deoxy-D-glucose, suggesting a glycolysis-dependent effect of PP2A in gastric cancer. Mechanistically, the well-known transcription factor and glycolysis regulator c-Myc was discovered as the functional mediator of PP2A in regulating cell glycolysis. Ectopic expression of a phosphorylation-mutant c-Myc resistant to PP2A (MycT58A) restored the inhibitory effect of FTY-720 and DT-061 on lactate production and glucose uptake. Furthermore, there was a close association between SET and CIP2A expression and c-Myc gene signatures in gastric cancer samples. Collectively, this study provides strong evidence of the involvement of PP2A in the Warburg effect and indicates that it could be a novel antitumor strategy to target tumor metabolism in gastric cancer.

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References

  1. Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144, 646–674.

    Article  CAS  PubMed  Google Scholar 

  2. Cairns, R. A., Harris, I. S., & Mak, T. W. (2011). Regulation of cancer cell metabolism. Nature reviews. Cancer, 11, 85–95.

    Article  CAS  PubMed  Google Scholar 

  3. Li, R., Li, H., Zhu, L., Zhang, X., Liu, D., Li, Q., Ni, B., Hu, L., Zhang, Z., Zhang, Y., Wang, X., & Jiang, S. H. (2021). Reciprocal regulation of LOXL2 and HIF1alpha drives the Warburg effect to support pancreatic cancer aggressiveness. Cell Death & Disease, 12, 1106.

    Article  CAS  Google Scholar 

  4. Yuan, Y., Ni, S., Zhuge, A., Li, B., & Li, L. (2021). Iron regulates the warburg effect and ferroptosis in colorectal cancer. Frontiers in Oncology, 11, 614778.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Jiang, S. H., Li, J., Dong, F. Y., Yang, J. Y., Liu, D. J., Yang, X. M., Wang, Y. H., Yang, M. W., Fu, X. L., Zhang, X. X., Li, Q., Pang, X. F., Huo, Y. M., Li, J., Zhang, J. F., Lee, H. Y., Lee, S. J., Qin, W. X., Gu, J. R., Sun, Y. W., & Zhang, Z. G. (2017). Increased serotonin signaling contributes to the Warburg effect in pancreatic tumor cells under metabolic stress and promotes growth of pancreatic tumors in mice. Gastroenterology, 153, 277–291 e219.

    Article  CAS  PubMed  Google Scholar 

  6. Hosios, A. M., & Manning, B. D. (2021). Cancer signaling drives cancer metabolism: AKT and the Warburg effect. Cancer Research, 81, 4896–4898.

    Article  CAS  PubMed  Google Scholar 

  7. Liu, C., Jin, Y., & Fan, Z. (2021). The mechanism of Warburg effect-induced chemoresistance in cancer. Frontiers in Oncology, 11, 698023.

    Article  PubMed  PubMed Central  Google Scholar 

  8. O’Connor, C. M., Perl, A., Leonard, D., Sangodkar, J., & Narla, G. (2018). Therapeutic targeting of PP2A. The International Journal of Biochemistry & Cell Biology, 96, 182–193.

    Article  Google Scholar 

  9. Shi, Y. (2009). Serine/threonine phosphatases: mechanism through structure. Cell, 139, 468–484.

    Article  CAS  PubMed  Google Scholar 

  10. Soofiyani, S. R., Hejazi, M. S., & Baradaran, B. (2017). The role of CIP2A in cancer: A review and update. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 96, 626–633.

    Article  CAS  Google Scholar 

  11. Mazhar, S., Taylor, S. E., Sangodkar, J., & Narla, G. (2019). Targeting PP2A in cancer: Combination therapies. Biochimica et Biophysica Acta. Molecular Cell Research, 1866, 51–63.

    Article  CAS  PubMed  Google Scholar 

  12. Liu, C. Y., Huang, T. T., Chen, Y. T., Chen, J. L., Chu, P. Y., Huang, C. T., Wang, W. L., Lau, K. Y., Dai, M. S., Shiau, C. W., & Tseng, L. M. (2019). Targeting SET to restore PP2A activity disrupts an oncogenic CIP2A-feedforward loop and impairs triple negative breast cancer progression. EBioMedicine, 40, 263–275.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kauko, O., & Westermarck, J. (2018). Non-genomic mechanisms of protein phosphatase 2A (PP2A) regulation in cancer. The International Journal of Biochemistry & Cell Biology, 96, 157–164.

    Article  CAS  Google Scholar 

  14. Goguet-Rubio, P., Amin, P., Awal, S., Vigneron, S., Charrasse, S., Mechali, F., Labbe, J. C., Lorca, T., & Castro, A. (2020). PP2A-B55 holoenzyme regulation and cancer. Biomolecules, 10, 1586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bao, Y., Oguz, G., Lee, W. C., Lee, P. L., Ghosh, K., Li, J., Wang, P., Lobie, P. E., Ehmsen, S., Ditzel, H. J., Wong, A., Tan, E. Y., Lee, S. C., & Yu, Q. (2020). EZH2-mediated PP2A inactivation confers resistance to HER2-targeted breast cancer therapy. Nature Communications, 11, 5878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Coles, G. L., Cristea, S., Webber, J. T., Levin, R. S., Moss, S. M., He, A., Sangodkar, J., Hwang, Y. C., Arand, J., Drainas, A. P., Mooney, N. A., Demeter, J., Spradlin, J. N., Mauch, B., Le, V., Shue, Y. T., Ko, J. H., Lee, M. C., Kong, C., Nomura, D. K., Ohlmeyer, M., Swaney, D. L., Krogan, N. J., Jackson, P. K., Narla, G., Gordan, J. D., Shokat, K. M., & Sage, J. (2020). Unbiased proteomic profiling uncovers a targetable GNAS/PKA/PP2A axis in small cell lung cancer stem cells. Cancer Cell, 38, 129–143 e127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Uddin, M. H., Pimentel, J. M., Chatterjee, M., Allen, J. E., Zhuang, Z., & Wu, G. S. (2020). Targeting PP2A inhibits the growth of triple-negative breast cancer cells. Cell Cycle, 19, 592–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tang, Z., Li, C., Kang, B., Gao, G., Li, C., & Zhang, Z. (2017). GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Research, 45, W98–W102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Vicente, C., Arriazu, E., Martinez-Balsalobre, E., Peris, I., Marcotegui, N., Garcia-Ramirez, P., Pippa, R., Rabal, O., Oyarzabal, J., Guruceaga, E., Prosper, F., Mateos, M. C., Cayuela, M. L., & Odero, M. D. (2020). A novel FTY720 analogue targets SET-PP2A interaction and inhibits growth of acute myeloid leukemia cells without inducing cardiac toxicity. Cancer Letters, 468, 1–13.

    Article  CAS  PubMed  Google Scholar 

  20. Hirata, N., Yamada, S., Yanagida, S., Ono, A., & Kanda, Y. (2021). FTY720 inhibits expansion of breast cancer stem cells via PP2A activation. International Journal of Molecular Sciences, 22, 7259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kauko, O., O’Connor, C. M., Kulesskiy, E., Sangodkar, J., Aakula, A., Izadmehr, S., Yetukuri, L., Yadav, B., Padzik, A., Laajala, T. D., Haapaniemi, P., Momeny, M., Varila, T., Ohlmeyer, M., Aittokallio, T., Wennerberg, K., Narla, G., & Westermarck, J. (2018). PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells. Science Translational Medicine, 10, eaaq1093.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Liu, Z., Yoshimi, A., Wang, J., Cho, H., Chun-Wei Lee, S., Ki, M., Bitner, L., Chu, T., Shah, H., Liu, B., Mato, A. R., Ruvolo, P., Fabbri, G., Pasqualucci, L., Abdel-Wahab, O., & Rabadan, R. (2020). Mutations in the RNA splicing factor SF3B1 promote tumorigenesis through MYC stabilization. Cancer Discovery, 10, 806–821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dang, C. V. (2012). MYC on the path to cancer. Cell, 149, 22–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Allen-Petersen, B. L., Risom, T., Feng, Z., Wang, Z., Jenny, Z. P., Thoma, M. C., Pelz, K. R., Morton, J. P., Sansom, O. J., Lopez, C. D., Sheppard, B., Christensen, D. J., Ohlmeyer, M., Narla, G., & Sears, R. C. (2019). Activation of PP2A and inhibition of mTOR synergistically reduce MYC signaling and decrease tumor growth in pancreatic ductal adenocarcinoma. Cancer Research, 79, 209–219.

    Article  CAS  PubMed  Google Scholar 

  25. Sangodkar, J., Perl, A., Tohme, R., Kiselar, J., Kastrinsky, D. B., Zaware, N., Izadmehr, S., Mazhar, S., Wiredja, D. D., O’Connor, C. M., Hoon, D., Dhawan, N. S., Schlatzer, D., Yao, S., Leonard, D., Borczuk, A. C., Gokulrangan, G., Wang, L., Svenson, E., Farrington, C. C., Yuan, E., Avelar, R. A., Stachnik, A., Smith, B., Gidwani, V., Giannini, H. M., McQuaid, D., McClinch, K., Wang, Z., Levine, A. C., Sears, R. C., Chen, E. Y., Duan, Q., Datt, M., Haider, S., Ma’ayan, A., DiFeo, A., Sharma, N., Galsky, M. D., Brautigan, D. L., Ioannou, Y. A., Xu, W., Chance, M. R., Ohlmeyer, M., & Narla, G. (2017). Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth, The. Journal of Clinical Investigation, 127, 2081–2090.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Sangodkar, J., Farrington, C. C., McClinch, K., Galsky, M. D., Kastrinsky, D. B., & Narla, G. (2016). All roads lead to PP2A: exploiting the therapeutic potential of this phosphatase. The FEBS Journal, 283, 1004–1024.

    Article  CAS  PubMed  Google Scholar 

  27. Enjoji, S., Yabe, R., Tsuji, S., Yoshimura, K., Kawasaki, H., Sakurai, M., Sakai, Y., Takenouchi, H., Yoshino, S., Hazama, S., Nagano, H., Oshima, H., Oshima, M., Vitek, M. P., Matsuura, T., Hippo, Y., Usui, T., Ohama, T., & Sato, K. (2018). Stemness is enhanced in gastric cancer by a SET/PP2A/E2F1 axis. Molecular Cancer Research: MCR, 16, 554–563.

    Article  CAS  PubMed  Google Scholar 

  28. Wang, J., Okkeri, J., Pavic, K., Wang, Z., Kauko, O., Halonen, T., Sarek, G., Ojala, P. M., Rao, Z., Xu, W., & Westermarck, J. (2017). Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56. EMBO Reports, 18, 437–450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Khanna, A., Bockelman, C., Hemmes, A., Junttila, M. R., Wiksten, J. P., Lundin, M., Junnila, S., Murphy, D. J., Evan, G. I., Haglund, C., Westermarck, J., & Ristimaki, A. (2009). MYC-dependent regulation and prognostic role of CIP2A in gastric cancer. Journal of the National Cancer Institute, 101, 793–805.

    Article  CAS  PubMed  Google Scholar 

  30. Li, W., Ge, Z., Liu, C., Liu, Z., Bjorkholm, M., Jia, J., & Xu, D. (2008). CIP2A is overexpressed in gastric cancer and its depletion leads to impaired clonogenicity, senescence, or differentiation of tumor cells, Clinical cancer research: an official journal of the American Association for. Cancer Research, 14, 3722–3728.

    CAS  Google Scholar 

  31. Zheng, T., Meng, X., Wang, J., Chen, X., Yin, D., Liang, Y., Song, X., Pan, S., Jiang, H., & Liu, L. (2010). PTEN- and p53-mediated apoptosis and cell cycle arrest by FTY720 in gastric cancer cells and nude mice. Journal of Cellular Biochemistry, 111, 218–228.

    Article  CAS  PubMed  Google Scholar 

  32. Scarpa, M., Singh, P., Bailey, C. M., Lee, J. K., Kapoor, S., Lapidus, R. G., Niyongere, S., Sangodkar, J., Wang, Y., Perrotti, D., Narla, G., & Baer, M. R. (2021). PP2A-activating drugs enhance FLT3 inhibitor efficacy through AKT inhibition-dependent GSK-3beta-Mediated c-Myc and Pim-1 proteasomal degradation. Molecular Cancer Therapeutics, 20, 676–690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang, L., Zhou, H., Li, X., Vartuli, R. L., Rowse, M., Xing, Y., Rudra, P., Ghosh, D., Zhao, R., & Ford, H. L. (2018). Eya3 partners with PP2A to induce c-Myc stabilization and tumor progression. Nature Communications, 9, 1047.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Tan, J., Lee, P. L., Li, Z., Jiang, X., Lim, Y. C., Hooi, S. C., & Yu, Q. (2010). B55beta-associated PP2A complex controls PDK1-directed myc signaling and modulates rapamycin sensitivity in colorectal cancer. Cancer Cell, 18, 459–471.

    Article  CAS  PubMed  Google Scholar 

  35. Janghorban, M., Farrell, A. S., Allen-Petersen, B. L., Pelz, C., Daniel, C. J., Oddo, J., Langer, E. M., Christensen, D. J., & Sears, R. C. (2014). Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 111, 9157–9162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Farrington, C. C., Yuan, E., Mazhar, S., Izadmehr, S., Hurst, L., Allen-Petersen, B. L., Janghorban, M., Chung, E., Wolczanski, G., Galsky, M., Sears, R., Sangodkar, J., & Narla, G. (2020). Protein phosphatase 2A activation as a therapeutic strategy for managing MYC-driven cancers. The Journal of Biological Chemistry, 295, 757–770.

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank all members of Department of General Surgery Clinic 2, Handan Central Hospital for assistance with this study.

Funding

This work was supported by grant from Hebei Provincial Health Commission (20220359).

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  1. These authors contributed equally: Zhenhua Cai, Wei Zhang

Authors and Affiliations

  1. Department of Operating Room, Handan Central Hospital, Handan, 056001, Hebei Province, China

    Zhenhua Cai

  2. Department of General Surgery Clinic 7, Handan Central Hospital, Handan, 056001, Hebei Province, China

    Wei Zhang, Yuhong Wang & Yunzhang Feng

  3. Handan Hanshan District Center for Disease Control and Prevention, Handan, 056001, Hebei Province, China

    Ruiqing Zhou

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  1. Zhenhua Cai
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Cai, Z., Zhang, W., Zhou, R. et al. Protein Phosphatase 2a Inhibits Gastric Cancer Cell Glycolysis by Reducing MYC Signaling. Cell Biochem Biophys 81, 59–68 (2023). https://doi.org/10.1007/s12013-022-01112-1

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