Knockdown of PROM2 Enhances Paclitaxel Sensitivity in Endometrial Cancer Cells by Regulating the AKT/FOXO1 Pathway


Citar

Texto integral

Resumo

Background: Endometrial cancer is a very common and highly lethal reproductive malignant tumour in women. Paclitaxel (PTX) is a usual drug utilized in chemotherapy for endometrial cancer. It has been uncovered that PROM2 participates in the progression of various cancers through playing a promoter. However, the regulatory function of PROM2 in PTX treatment for endometrial cancer remains unclear.

Methods: The cell viability (IC50) was examined through CCK8 assay. The mRNA and protein expressions of genes were measured through RT-qPCR and western blot. The proliferation was evaluated through colony formation and EdU assays. The cell apoptosis was assessed through flow cytometry.

Results: In this work, through bioinformatic analysis on online websites, it is found that the up-regulated expression of PROM2 existed in endometrial cancer. In addition, the survival probability of UCEC patients with high PROM2 expression was worse. This study adopted PTX treatment for obtaining the PTX-resistant cells (HEC-1A/PTX and KLE/PTX). Furthermore, suppression of PROM2 enhanced PTX sensitivity through decreasing IC50 and proliferation in endometrial cancer. Additionally, knockdown of PROM2 facilitated cell apoptosis in HEC-1A/PTX and KLE/PTX cells. Next, we found that silencing of PROM2 retards the AKT/FOXO1 pathway. At last, rescue assays reversed the strengthened PTX sensitivity mediated by PROM2 inhibition after SC79 treatment (AKT activator).

Conclusion: Knockdown of PROM2 enhanced PTX sensitivity in endometrial cancer through modulating the AKT/FOXO1 pathway. This study hinted that PROM2 may be a useful therapeutic target for PTX treatment in endometrial cancer.

Sobre autores

Jun Jiang

Department of Gynecology, The First Affiliated Hospital of Zhejiang Chinese Medical University

Email: info@benthamscience.net

Chen Zhang

Department of Gynecology, The First Affiliated Hospital of Zhejiang Chinese Medical University

Email: info@benthamscience.net

Jianfen Wang

Department of Gynecology,, The First Affiliated Hospital of Zhejiang Chinese Medical Universit y

Email: info@benthamscience.net

Yingping Zhu

Department of Gynecology, The First Affiliated Hospital of Zhejiang Chinese Medical Universit y

Email: info@benthamscience.net

Xinyan Wang

Department of Gynecology, The First Affiliated Hospital of Zhejiang Chinese Medical University

Email: info@benthamscience.net

Peiyu Mao

Department of Gynecology, The First Affiliated Hospital of Zhejiang Chinese Medical University

Autor responsável pela correspondência
Email: info@benthamscience.net

Bibliografia

  1. Amant, F.; Moerman, P.; Neven, P.; Timmerman, D.; Van Limbergen, E.; Vergote, I. Endometrial cancer. Lancet, 2005, 366(9484), 491-505. doi: 10.1016/S0140-6736(05)67063-8 PMID: 16084259
  2. Bakir, M.S.; Birge, O.; Karadag, C.; Dogan, S.; Tuncer, H.A.; Simsek, T. Clinicopathological risk factors and survival analysis of ovarian cancer with synchronous endometrial cancer diagnosed after surgery. Eur. J. Gynaecol. Oncol., 2021, 42(3), 499-505. doi: 10.31083/j.ejgo.2021.03.2336
  3. Wan-Nor-Asyikeen, W.A.; Siti-Azrin, A.H.; Jalil, N.A.; Othman, N.H.; Zain, A.A. Endometrial cancer in hospital universiti sains malaysia. Asian Pac. J. Cancer Prev., 2016, 17(6), 2867-2870. PMID: 27356704
  4. Braun, M.M.; Overbeek-Wager, E.A.; Grumbo, R.J. Diagnosis and management of endometrial cancer. Am. Fam. Physician, 2016, 93(6), 468-474. PMID: 26977831
  5. Her, E-J.; Kwon, H.; Chae, B.; Kim, Y-J.; Lee, Y-S. High D-dimer is a predictor for short-term mortality in patients with active cancer and acute pulmonary embolism. Signa Vitae, 2021, 17(5), 58-63.
  6. Kim, M.K.; Choi, M.C.; Lim, M.C.; Kim, J-W. Practice patterns for Lynch syndrome-associated endometrial cancer management in Korea. Eur. J. Gynaecol. Oncol., 2021, 42(4), 737-741. doi: 10.31083/j.ejgo4204111
  7. Pérez-Herrero, E.; Fernández-Medarde, A. Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy. Eur. J. Pharm. Biopharm., 2015, 93, 52-79. doi: 10.1016/j.ejpb.2015.03.018 PMID: 25813885
  8. Gómez-Raposo, C.; Merino Salvador, M.; Aguayo Zamora, C.; Casado Saenz, E. Adjuvant chemotherapy in endometrial cancer. Cancer Chemother. Pharmacol., 2020, 85(3), 477-486. doi: 10.1007/s00280-019-04027-6 PMID: 31950214
  9. Bestvina, C.M.; Fleming, G.F. Chemotherapy for endometrial cancer in adjuvant and advanced disease settings. Oncologist, 2016, 21(10), 1250-1259. doi: 10.1634/theoncologist.2016-0062 PMID: 27412393
  10. Saha, S.K.; Islam, S.M.R.; Kwak, K.S.; Rahman, M.S.; Cho, S.G. PROM1 and PROM2 expression differentially modulates clinical prognosis of cancer: A multiomics analysis. Cancer Gene Ther., 2020, 27(3-4), 147-167. doi: 10.1038/s41417-019-0109-7 PMID: 31164716
  11. Lee, J.; Shin, J.E.; Lee, B.; Kim, H.; Jeon, Y.; Ahn, S.H.; Chi, S.W.; Cho, Y. The stem cell marker Prom1 promotes axon regeneration by down-regulating cholesterol synthesis via Smad signaling. Proc. Natl. Acad. Sci. USA, 2020, 117(27), 15955-15966. doi: 10.1073/pnas.1920829117 PMID: 32554499
  12. Florek, M.; Bauer, N.; Janich, P.; Wilsch-Braeuninger, M.; Fargeas, C.A.; Marzesco, A.M.; Ehninger, G.; Thiele, C.; Huttner, W.B.; Corbeil, D. Prominin-2 is a cholesterol-binding protein associated with apical and basolateral plasmalemmal protrusions in polarized epithelial cells and released into urine. Cell Tissue Res., 2007, 328(1), 31-47. doi: 10.1007/s00441-006-0324-z PMID: 17109118
  13. Barzegar Behrooz, A.; Syahir, A.; Ahmad, S. CD133: Beyond a cancer stem cell biomarker. J. Drug Target., 2019, 27(3), 257-269. doi: 10.1080/1061186X.2018.1479756 PMID: 29911902
  14. Li, W.; Zhu, Y.; Zhang, K.; Yu, X.; Lin, H.; Wu, W.; Peng, Y.; Sun, J. PROM2 promotes gemcitabine chemoresistance via activating the Akt signaling pathway in pancreatic cancer. Exp. Mol. Med., 2020, 52(3), 409-422. doi: 10.1038/s12276-020-0390-4 PMID: 32123287
  15. Luo, W.; Wang, J.; Xu, W.; Ma, C.; Wan, F.; Huang, Y.; Yao, M.; Zhang, H.; Qu, Y.; Ye, D.; Zhu, Y. LncRNA RP11-89 facilitates tumorigenesis and ferroptosis resistance through PROM2-activated iron export by sponging miR-129-5p in bladder cancer. Cell Death Dis., 2021, 12(11), 1043. doi: 10.1038/s41419-021-04296-1 PMID: 34728613
  16. Bao, L.; Zhang, Y.; Wang, J.; Wang, H.; Dong, N.; Su, X.; Xu, M.; Wang, X. Variations of chromosome 2 gene expressions among patients with lung cancer or non-cancer. Cell Biol. Toxicol., 2016, 32(5), 419-435. doi: 10.1007/s10565-016-9343-z PMID: 27301951
  17. Yen, T.T.; Wang, T.L.; Fader, A.N.; Shih, I.M.; Gaillard, S. Molecular classification and emerging targeted therapy in endometrial cancer. Int. J. Gynecol. Pathol., 2020, 39(1), 26-35. doi: 10.1097/PGP.0000000000000585
  18. Zarrin, H.; Ko, E.; Haggerty, A.; Latif, N.; Kim, S.; Cory, L. Comparative survival outcomes among high risk endometrial cancers. Eur. J. Gynaecol. Oncol., 2021, 42(2), 386-387.
  19. Alqahtani, F.Y.; Aleanizy, F.S.; El Tahir, E.; Alkahtani, H.M.; AlQuadeib, B.T. Paclitaxel. Profiles Drug Subst. Excip. Relat. Methodol., 2019, 44, 205-238. doi: 10.1016/bs.podrm.2018.11.001 PMID: 31029218
  20. Chaudhry, P.; Asselin, E. Resistance to chemotherapy and hormone therapy in endometrial cancer. Endocr. Relat. Cancer, 2009, 16(2), 363-380. doi: 10.1677/ERC-08-0266 PMID: 19190080
  21. Fernandes, C.; Prabhu, P.; Juvale, K.; Suares, D.; Yc, M. Cancer cell fusion: A potential target to tackle drug-resistant and metastatic cancer cells. Drug Discov. Today, 2019, 24(9), 1836-1844. doi: 10.1016/j.drudis.2019.05.024 PMID: 31163272
  22. Bruce, S.F.; Cho, K.; Noia, H.; Lomonosova, E.; Stock, E.C.; Oplt, A.; Blachut, B.; Mullen, M.M.; Kuroki, L.M.; Hagemann, A.R.; McCourt, C.K.; Thaker, P.H.; Khabele, D.; Powell, M.A.; Mutch, D.G.; Shriver, L.P.; Patti, G.J.; Fuh, K.C. GAS6-AXL inhibition by AVB-500 overcomes resistance to paclitaxel in endometrial cancer by decreasing tumor cell glycolysis. Mol. Cancer Ther., 2022, 21(8), 1348-1359. doi: 10.1158/1535-7163.MCT-21-0704 PMID: 35588308
  23. Yanokura, M.; Banno, K.; Aoki, D. MicroRNA 34b expression enhances chemosensitivity of endometrial cancer cells to paclitaxel. Int. J. Oncol., 2020, 57(5), 1145-1156. doi: 10.3892/ijo.2020.5127 PMID: 33300049
  24. Yi, H.; Han, Y.; Li, S. Oncogenic circular RNA circ_0007534 contributes to paclitaxel resistance in endometrial cancer by sponging miR-625 and promoting ZEB2 expression. Front. Oncol., 2022, 12, 985470. doi: 10.3389/fonc.2022.985470 PMID: 35992812
  25. Abraham, E. Akt/protein kinase B. Crit. Care Med., 2005, 33(12)(Suppl.), S420-S422. doi: 10.1097/01.CCM.0000191715.31970.D8 PMID: 16340410
  26. Qiu, J.; Zhang, Y.; Xie, M. Chrysotoxine attenuates sevoflurane-induced neurotoxicity in vitro via regulating PI3K/AKT/GSK pathway. Signa Vitae, 2021, 17(4), 185-191.
  27. Liao, J.; Chen, H.; Qi, M.; Wang, J.; Wang, M. MLLT11-TRIL complex promotes the progression of endometrial cancer through PI3K/AKT/mTOR signaling pathway. Cancer Biol. Ther., 2022, 23(1), 211-224. doi: 10.1080/15384047.2022.2046450 PMID: 35253622
  28. Link, W. Introduction to FOXO Biology. Methods Mol. Biol., 2019, 1890, 1-9. doi: 10.1007/978-1-4939-8900-3_1 PMID: 30414140
  29. Xing, Y.; Li, A.; Yang, Y.; Li, X.; Zhang, L.; Guo, H. The regulation of FOXO1 and its role in disease progression. Life Sci., 2018, 193, 124-131. doi: 10.1016/j.lfs.2017.11.030 PMID: 29158051
  30. Ma, L.; Sun, Y.; Li, D.; Li, H.; Jin, X.; Ren, D. Overexpressed ITGA2 contributes to paclitaxel resistance by ovarian cancer cells through the activation of the AKT/FoxO1 pathway. Aging (Albany NY), 2020, 12(6), 5336-5351. doi: 10.18632/aging.102954 PMID: 32202508
  31. Lu, Z.; Xu, Y.; Yao, Y.; Jiang, S. miR-205-5p contributes to paclitaxel resistance and progression of endometrial cancer by downregulating FOXO1. Oncol. Res., 2019. Epub ahead of print doi: 10.3727/096504018X15452187888839 PMID: 30982496

Arquivos suplementares

Arquivos suplementares
Ação
1. JATS XML
Baixar

Declaração de direitos autorais © Bentham Science Publishers, 2023