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PIM2 Promotes the Development of Ovarian Endometriosis by Enhancing Glycolysis and Fibrosis

  • Endometriosis: Original Article
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Abstract

Endometriosis is a common gynecological disorder characterized by the presence of the endometrial glands and the stroma outside the uterine cavity. The disease affects reproductive function and quality of life in women of reproductive age. Endometriosis is similar to tumors in some characteristics, such as glycolysis. PIM2 can promote the development of tumors, but the mechanism of PIM2 in endometriosis is still unclear. Therefore, our goal is to study the mechanism of PIM2 in endometriosis. Through immunohistochemistry, we found PIM2, HK2, PKM2, SMH (smooth muscle myosin heavy chain), Desmin, and α-SMA (α-smooth muscle actin) were strongly expressed in the ovarian endometriosis. In endometriotic cells, PIM2 enhanced glycolysis and fibrosis via upregulating the expression of PKM2. Moreover, the PIM2 inhibitor SMI-4a inhibited the development of endometriosis. And we established a PIM2 knockout mouse model of endometriosis to demonstrate the role of PIM2 in vivo. In summary, our study indicates that PIM2 promotes the development of endometriosis. PIM2 may serve as a promising therapeutic target for endometriosis.

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The data underlying this article will be shared at reasonable request to the corresponding author.

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References

  1. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3):511–9.

    Article  CAS  PubMed  Google Scholar 

  2. Patzkowsky K. Rethinking endometriosis and pelvic pain. J Clin Invest. 2021;131(20):e154876.

  3. Vercellini P, Vigano P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10(5):261–75.

    Article  CAS  PubMed  Google Scholar 

  4. Laganà AS, Garzon S, Götte M, Viganò P, Franchi M, Ghezzi F, et al. The pathogenesis of endometriosis: molecular and cell biology insights. Int J Mol Sci. 2019;20(22):5615.

  5. Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. The Lancet. 2021;397(10276):839–52.

    Article  CAS  Google Scholar 

  6. Hang Y, Tan L, Chen Q, Liu Q, Jin Y. E3 ubiquitin ligase TRIM24 deficiency promotes NLRP3/caspase-1/IL-1beta-mediated pyroptosis in endometriosis. Cell Biol Int. 2021;45(7):1561–70.

    Article  CAS  PubMed  Google Scholar 

  7. Young VJ, Brown JK, Maybin J, Saunders PT, Duncan WC, Horne AW. Transforming growth factor-beta induced Warburg-like metabolic reprogramming may underpin the development of peritoneal endometriosis. J Clin Endocrinol Metab. 2014;99(9):3450–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ganapathy-Kanniappan S, Geschwind JF. Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol Cancer. 2013;12:152.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mikawa T, Lleonart ME, Takaori-Kondo A, Inagaki N, Yokode M, Kondoh H. Dysregulated glycolysis as an oncogenic event. Cell Mol Life Sci. 2015;72(10):1881–92.

  11. Kobayashi H, Shigetomi H, Imanaka S. Nonhormonal therapy for endometriosis based on energy metabolism regulation. Reprod Fertil. 2021;2(4):C42–57.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ding H, Jiang L, Xu J, Bai F, Zhou Y, Yuan Q, et al. Inhibiting aerobic glycolysis suppresses renal interstitial fibroblast activation and renal fibrosis. Am J Physiol Renal Physiol. 2017;313(3):F561–75.

    Article  CAS  PubMed  Google Scholar 

  13. Hu WP, Tay SK, Zhao Y. Endometriosis-specific genes identified by real-time reverse transcription-polymerase chain reaction expression profiling of endometriosis versus autologous uterine endometrium. J Clin Endocrinol Metab. 2006;91(1):228–38.

    Article  CAS  PubMed  Google Scholar 

  14. Blanco-Aparicio C, Carnero A. Pim kinases in cancer: diagnostic, prognostic and treatment opportunities. Biochem Pharmacol. 2013;85(5):629–43.

    Article  CAS  PubMed  Google Scholar 

  15. Yang T, Ren C, Qiao P, Han X, Wang L, Lv S, et al. PIM2-mediated phosphorylation of hexokinase 2 is critical for tumor growth and paclitaxel resistance in breast cancer. Oncogene. 2018;37(45):5997–6009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kronschnabl P, Grunweller A, Hartmann RK, Aigner A, Weirauch U. Inhibition of PIM2 in liver cancer decreases tumor cell proliferation in vitro and in vivo primarily through the modulation of cell cycle progression. Int J Oncol. 2020;56(2):448–59.

    CAS  PubMed  Google Scholar 

  17. Tang X, Cao T, Zhu Y, Zhang L, Chen J, Liu T, et al. PIM2 promotes hepatocellular carcinoma tumorigenesis and progression through activating NF-kappaB signaling pathway. Cell Death Dis. 2020;11(7):510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang F, Xu L, Dong G, Zhu M, Liu L, Wang B. PIM2 deletion alleviates lipopolysaccharide (LPS)-induced respiratory distress syndrome (ARDS) by suppressing NLRP3 inflammasome. Biochem Biophys Res Commun. 2020;533(4):1419–26.

    Article  CAS  PubMed  Google Scholar 

  19. Wang L, Chen Y, Wu S, Wang L, Tan F, Li F. PIM2-mediated phosphorylation contributes to granulosa cell survival via resisting apoptosis during folliculogenesis. Clin Transl Med. 2021;11(3): e359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Han X, Ren C, Yang T, Qiao P, Wang L, Jiang A, et al. Negative regulation of AMPKalpha1 by PIM2 promotes aerobic glycolysis and tumorigenesis in endometrial cancer. Oncogene. 2019;38(38):6537–49.

    Article  CAS  PubMed  Google Scholar 

  21. Yu Z, Zhao X, Huang L, Zhang T, Yang F, Xie L, et al. Proviral insertion in murine lymphomas 2 (PIM2) oncogene phosphorylates pyruvate kinase M2 (PKM2) and promotes glycolysis in cancer cells. J Biol Chem. 2013;288(49):35406–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zeitvogel A, Baumann R, Starzinski-Powitz A. Identification of an invasive, N-cadherin-expressing epithelial cell type in endometriosis using a new cell culture model. Am J Pathol. 2001;159(5):1839–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ding D, Liu X, Duan J, Guo SW. Platelets are an unindicted culprit in the development of endometriosis: clinical and experimental evidence. Hum Reprod. 2015;30(4):812–32.

    Article  CAS  PubMed  Google Scholar 

  24. Lu C, Ren C, Yang T, Sun Y, Qiao P, Han X, et al. Fructose-1, 6-bisphosphatase 1 interacts with NF-kappaB p65 to regulate breast tumorigenesis via PIM2 induced phosphorylation. Theranostics. 2020;10(19):8606–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yang T, Ren C, Lu C, Qiao P, Han X, Wang L, et al. Phosphorylation of HSF1 by PIM2 induces PD-L1 expression and promotes tumor growth in breast cancer. Cancer Res. 2019;79(20):5233–44.

    Article  CAS  PubMed  Google Scholar 

  26. Yao Q, Jing G, Zhang X, Li M, Yao Q, Wang L. Cinnamic acid inhibits cell viability, invasion, and glycolysis in primary endometrial stromal cells by suppressing NF-kappaB-induced transcription of PKM2. Biosci Rep. 2021. https://doi.org/10.1042/BSR20211828.

  27. Mehedintu C, Plotogea MN, Ionescu S, Antonovici M. Endometriosis still a challenge. J Med Life. 2014;7(3):349–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Signorile PG, Baldi A. New evidence in endometriosis. Int J Biochem Cell Biol. 2015;60:19–22.

    Article  CAS  PubMed  Google Scholar 

  29. Zondervan KT, Becker CM, Koga K, Missmer SA, Taylor RN, Vigano P. Endometriosis Nat Rev Dis Primers. 2018;4(1):9.

    Article  PubMed  Google Scholar 

  30. Wang Y, Xiu J, Ren C, Yu Z. Protein kinase PIM2: a simple PIM family kinase with complex functions in cancer metabolism and therapeutics. J Cancer. 2021;12(9):2570–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Warmoes MO, Locasale JW. Heterogeneity of glycolysis in cancers and therapeutic opportunities. Biochem Pharmacol. 2014;92(1):12–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Levine AJ, Puzio-Kuter AM. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science. 2010;330(6009):1340–4.

    Article  CAS  PubMed  Google Scholar 

  33. McDonald JE, Kessler MM, Gardner MW, Buros AF, Ntambi JA, Waheed S, et al. Assessment of total lesion glycolysis by (18)F FDG PET/CT significantly improves prognostic value of GEP and ISS in myeloma. Clin Cancer Res. 2017;23(8):1981–7.

    Article  CAS  PubMed  Google Scholar 

  34. Brandes RP, Rezende F. Glycolysis and inflammation: partners in crime! Circ Res. 2021;129(1):30–2.

    Article  CAS  PubMed  Google Scholar 

  35. Erlich JR, To EE, Luong R, Liong F, Liong S, Oseghale O, et al. Glycolysis and the pentose phosphate pathway promote LPS-induced NOX2 oxidase- and IFN-beta-dependent inflammation in macrophages. Antioxidants (Basel). 2022;11(8):1488.

  36. Wang S, Yu H, Gao J, Chen J, He P, Zhong H, et al. PALMD regulates aortic valve calcification via altered glycolysis and NF-kappaB-mediated inflammation. J Biol Chem. 2022;298(5): 101887.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wong N, De Melo J, Tang D. PKM2, a central point of regulation in cancer metabolism. Int J Cell Biol. 2013;2013: 242513.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zhang Z, Deng X, Liu Y, Liu Y, Sun L, Chen F. PKM2, function and expression and regulation. Cell Biosci. 2019;9:52.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Zhang Q, Duan J, Olson M, Fazleabas A, Guo SW. Cellular changes consistent with epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the progression of experimental endometriosis in baboons. Reprod Sci. 2016;23(10):1409–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ganieva U, Nakamura T, Osuka S, Bayasula, Nakanishi N, Kasahara Y, et al. Involvement of transcription factor 21 in the pathogenesis of fibrosis in endometriosis. Am J Pathol. 2020;190(1):145–57.

  41. Vigano P, Candiani M, Monno A, Giacomini E, Vercellini P, Somigliana E. Time to redefine endometriosis including its pro-fibrotic nature. Hum Reprod. 2018;33(3):347–52.

    Article  CAS  PubMed  Google Scholar 

  42. Zeng X, Yue Z, Gao Y, Jiang G, Zeng F, Shao Y, et al. NR4A1 is involved in fibrogenesis in ovarian endometriosis. Cell Physiol Biochem. 2018;46(3):1078–90.

    Article  CAS  PubMed  Google Scholar 

  43. Direkze NC, Forbes SJ, Brittan M, Hunt T, Jeffery R, Preston SL, et al. Multiple organ engraftment by bone-marrow-derived myofibroblasts and fibroblasts in bone-marrow-transplanted mice. Stem Cells. 2003;21(5):514–20.

    Article  PubMed  Google Scholar 

  44. Higashiyama R, Nakao S, Shibusawa Y, Ishikawa O, Moro T, Mikami K, et al. Differential contribution of dermal resident and bone marrow-derived cells to collagen production during wound healing and fibrogenesis in mice. J Invest Dermatol. 2011;131(2):529–36.

    Article  CAS  PubMed  Google Scholar 

  45. Stone RC, Pastar I, Ojeh N, Chen V, Liu S, Garzon KI, et al. Epithelial-mesenchymal transition in tissue repair and fibrosis. Cell Tissue Res. 2016;365(3):495–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This research was supported by the National Natural Science Foundation of China (Nos. 81602301 and 81972489), Natural Science Foundation of Shandong Province (No. ZR2021MH235), Shandong province college science and technology plan project (No. J17KA254), and Clinical Research Center of Affiliated Hospital of Weifang Medical University (No. 2021wyfylcyj01).

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Author notes

  1. Mengxue Wang, Ruiqi Fan, and Junyi Jiang contributed equally to this work.

Authors and Affiliations

  1. Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, People’s Republic of China

    Mengxue Wang, Ruiqi Fan, Junyi Jiang, Fangyuan Sun, Yujun Sun, Qian Wang, Aifang Jiang, Zhenhai Yu & Tingting Yang

  2. School of Clinical Medicine, Weifang Medical University, Weifang, Shandong Province, People’s Republic of China

    Mengxue Wang, Ruiqi Fan, Fangyuan Sun, Yujun Sun & Qian Wang

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  1. Mengxue Wang
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Contributions

TY, ZY, MW, and RF designed the study. RF, JJ, and FS performed experiments. YS, QW, and AJ provided experimental and analytical support. ZY and TY supervised the study. MW and TY wrote and edited the manuscript with feedback from all authors.

Corresponding authors

Correspondence to Zhenhai Yu or Tingting Yang.

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Ethics Approval

Human Investigation Ethical Committee of Affiliated Hospital of Weifang Medical University approved this study (approved No. Wyfy-2022-ky-094).

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Wang, M., Fan, R., Jiang, J. et al. PIM2 Promotes the Development of Ovarian Endometriosis by Enhancing Glycolysis and Fibrosis. Reprod. Sci. 30, 2692–2702 (2023). https://doi.org/10.1007/s43032-023-01208-w

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