Downregulation of PDCD4 induced by progesterone is mediated by the PI3K/AKT signaling pathway in human endometrial cancer cells

Wang,Xishuang; Li,Yue; Wan,Lu; Liu,Yanping; Sun,Yingshuo; Liu,Yuqiu; Shi,Yongyu; Zhang,Lining; Zhou,Huaiyu; Wang,Jianing; Wang,Xiaoyan; Wei,Zengtao

doi:10.3892/or.2019.7202

Downregulation of PDCD4 induced by progesterone is mediated by the PI3K/AKT signaling pathway in human endometrial cancer cells

Authors:
- Xishuang Wang
- Yue Li
- Lu Wan
- Yanping Liu
- Yingshuo Sun
- Yuqiu Liu
- Yongyu Shi
- Lining Zhang
- Huaiyu Zhou
- Jianing Wang
- Xiaoyan Wang
- Zengtao Wei
View Affiliations

Affiliations: Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China, Department of Gynecology and Obstetrics, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China, Department of Microbiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China
Published online on: June 18, 2019 https://doi.org/10.3892/or.2019.7202
Pages: 849-856

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Programmed cell death 4 (PDCD4) has been identified as a tumor‑suppressor gene that inhibits neoplastic transformation, tumor progression, and protein translation. It has been reported that multiple factors participate in the regulation of PDCD4 mRNA and protein. The endometrium is regulated by changing concentrations of ovarian hormones, such as estrogen and progesterone, and shows periodical changes. However, whether ovarian hormones regulate PDCD4 expression remains unclear. This study aimed to explore the effect and mechanism of estrogen or progesterone on PDCD4 mRNA and protein expression in human endometrial cancer cells. The expression of PDCD4 mRNA and protein in Ishikawa and HEC‑1‑A cells was detected by quantitative real‑time PCR and western blot analysis. The signaling pathway‑related proteins were detected by western blot analysis. The results showed that PDCD4 mRNA levels exhibited no significant changes after treatment with estrogen or progesterone in both Ishikawa and HEC‑1‑A cell lines. Estrogen also had no obvious effect on PDCD4 protein expression. However, progesterone effectively decreased the expression of PDCD4 protein and the PI3K/AKT pathway may be involved in the downregulation of PDCD4 protein induced by progesterone. These results suggest that the downregulation of PDCD4 induced by progesterone affects the therapeutic efficacy of progesterone in human endometrial cancer or endometriosis, which may have important implications for progesterone treatment in the clinic.

View Figures

View References

1	Cmarik JL, Min H, Hegamyer G, Zhan S, Kulesz-Martin M, Yoshinaga H, Matsuhashi S and Colburn N: Differentially expressed protein Pdcd4 inhibits tumor promoter-induced neoplastic transformation. Proc Natl Acad Sci USA. 96:14037–14042. 1999. View Article : Google Scholar : PubMed/NCBI
2	Yang HS, Jansen AP, Nair R, Shibahara K, Verma AK, Cmarik JL and Colburn NH: A novel transformation suppressor, Pdcd4, inhibits AP-1 transactivation but not NF-kappaB or ODC transactivation. Oncogene. 20:669–676. 2001. View Article : Google Scholar : PubMed/NCBI
3	Ding L, Zhang X, Zhao M, Qu Z, Huang S, Dong M and Gao F: An essential role of PDCD4 in progression and malignant proliferation of gastrointestinal stromal tumors. Med Oncology. 29:1758–1764. 2012. View Article : Google Scholar
4	LaRonde-LeBlanc N, Santhanam AN, Baker AR, Wlodawer A and Colburn NH: Structural basis for inhibition of translation by the tumor suppressor Pdcd4. Mol Cell Biol. 27:147–156. 2007. View Article : Google Scholar : PubMed/NCBI
5	Lankat-Buttgereit B and Goke R: Programmed cell death protein 4 (pdcd4): A novel target for antineoplastic therapy? Biol Cell. 95:515–519. 2003. View Article : Google Scholar : PubMed/NCBI
6	Zhang H, Ozaki I, Mizuta T, Hamajima H, Yasutake T, Eguchi Y, Ideguchi H, Yamamoto K and Matsuhashi S: Involvement of programmed cell death 4 in transforming growth factor-beta1-induced apoptosis in human hepatocellular carcinoma. Oncogene. 25:6101–6112. 2006. View Article : Google Scholar : PubMed/NCBI
7	Chen Y, Knosel T, Kristiansen G, Pietas A, Garber ME, Matsuhashi S, Ozaki I and Petersen I: Loss of PDCD4 expression in human lung cancer correlates with tumour progression and prognosis. J Pathol. 200:640–646. 2003. View Article : Google Scholar : PubMed/NCBI
8	Wen YH, Shi X, Chiriboga L, Matsahashi S, Yee H and Afonja O: Alterations in the expression of PDCD4 in ductal carcinoma of the breast. Oncol Rep. 18:1387–1393. 2007.PubMed/NCBI
9	Wei NA, Liu SS, Leung TH, Tam KF, Liao XY, Cheung AN, Chan KK and Ngan HY: Loss of programmed cell death 4 (Pdcd4) associates with the progression of ovarian cancer. Mol Cancer. 8:702009. View Article : Google Scholar : PubMed/NCBI
10	Shibahara K, Asano M, Ishida Y, Aoki T, Koike T and Honjo T: Isolation of a novel mouse gene MA-3 that is induced upon programmed cell death. Gene. 166:297–301. 1995. View Article : Google Scholar : PubMed/NCBI
11	Lankat-Buttgereit B and Goke R: The tumour suppressor Pdcd4: Recent advances in the elucidation of function and regulation. Biol Cell. 101:309–317. 2009. View Article : Google Scholar : PubMed/NCBI
12	Onishi Y and Kizaki H: Molecular cloning of the genes suppressed in RVC lymphoma cells by topoisomerase inhibitors. Biochem Biophysical Res Commun. 228:7–13. 1996. View Article : Google Scholar
13	Azzoni L, Zatsepina O, Abebe B, Bennett IM, Kanakaraj P and Perussia B: Differential transcriptional regulation of CD161 and a novel gene, 197/15a, by IL-2, IL-15, and IL-12 in NK and T cells. J Immunol. 161:3493–3500. 1998.PubMed/NCBI
14	Mundim TC, Ramos AF, Sartori R, Dode MA, Melo EO, Gomes LF, Rumpf R and Franco MM: Changes in gene expression profiles of bovine embryos produced in vitro, by natural ovulation, or hormonal superstimulation. Genet Mol Res. 8:1398–1407. 2009. View Article : Google Scholar : PubMed/NCBI
15	Qin X, Zhang H, Wang F, Xue J and Wen Z: Expression and possible role of interleukin-10 receptors in patients with adenomyosis. Eur j Obstet Gynecol Rep Biol. 161:194–198. 2012. View Article : Google Scholar
16	Lin SL, Yan LY, Zhang XT, Yuan J, Li M, Qiao J, Wang ZY and Sun QY: ER-alpha36, a variant of ER-alpha, promotes tamoxifen agonist action in endometrial cancer cells via the MAPK/ERK and PI3K/Akt pathways. PLoS One. 5:e90132010. View Article : Google Scholar : PubMed/NCBI
17	Liu Y, Tan X, Wang Z, Li Y, Gao M, Li Y, Fang Z, Sun Y, Zhang L, Wang X and Wei Z: Down-regulation of tumor suppressor PDCD4 expression in endometrium of adenomyosis patients. Curr Res Transl Med. 64:123–128. 2016. View Article : Google Scholar : PubMed/NCBI
18	Li N, Wang J, Zhang N, Zhuang M, Zong Z, Zou J, Li G, Wang X, Zhou H, Zhang L and Shi Y: Cross-talk between TNF-α and IFN-γ signaling in induction of B7-H1 expression in hepatocellular carcinoma cells. Cancer Immunol Immunother. 271–283. 2018. View Article : Google Scholar : PubMed/NCBI
19	Pant A, Lee II, Lu Z, Rueda BR, Schink J and Kim JJ: Inhibition of AKT with the orally active allosteric AKT inhibitor, MK-2206, sensitizes endometrial cancer cells to progestin. PLoS One. 7:e415932012. View Article : Google Scholar : PubMed/NCBI
20	Nabilsi NH, Broaddus RR, McCampbell AS, Lu KH, Lynch HT, Chen LM and Loose DS: Sex hormone regulation of survivin gene expression. J Endocrinol. 207:237–243. 2010. View Article : Google Scholar : PubMed/NCBI
21	Bischof P, Krahenbuhl C and Desaulles PA: Elucidation of the mechanism responsible for the luteolytic effect of oestradiol during pseudogestation in the rat. Experientia. 30:1101–1102. 1974. View Article : Google Scholar : PubMed/NCBI
22	Knobil E: Hormonal control of the menstrual cycle and ovulation in the rhesus monkey. Acta Endocrinol Suppl (Copenh). 166:137–144. 1972. View Article : Google Scholar : PubMed/NCBI
23	Zhao Y, Gong P, Chen Y, Nwachukwu JC, Srinivasan S, Ko C, Bagchi MK, Taylor RN, Korach KS, Nettles KW, et al: Dual suppression of estrogenic and inflammatory activities for targeting of endometriosis. Sci Transl Med. 7:271ra92015. View Article : Google Scholar : PubMed/NCBI
24	Stadel BV: Estrogen therapy and endometrial carcinoma. Am J Obstet Gynecol. 125:571–573. 1976. View Article : Google Scholar : PubMed/NCBI
25	Fang Z, Yang S, Lydon JP, DeMayo F, Tamura M, Gurates B and Bulun SE: Intact progesterone receptors are essential to counteract the proliferative effect of estradiol in a genetically engineered mouse model of endometriosis. Ferti Steril. 82:673–678. 2004. View Article : Google Scholar
26	Cooke PS, Buchanan DL, Young P, Calhaz-Jorge C, D'Hooghe T, De Bie B, Heikinheimo O, Horne AW, Kiesel L and Nap A: Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium. Proc Natl Acad Sci USA. 94:6535–6540. 1997. View Article : Google Scholar : PubMed/NCBI
27	Li Y, Adur MK, Kannan A, Davila J, Zhao Y, Nowak RA, Bagchi MK, Bagchi IC and Li Q: Progesterone alleviates endometriosis via inhibition of uterine cell proliferation, inflammation and angiogenesis in an immunocompetent mouse model. PLoS One. 11:e01653472016. View Article : Google Scholar : PubMed/NCBI
28	Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D'Hooghe T, De Bie B, Heikinheimo O, Horne AW, Kiesel L, Nap A, et al: ESHRE guideline: Management of women with endometriosis. Hum Reprod. 29:400–412. 2014. View Article : Google Scholar : PubMed/NCBI
29	Mounsey AL, Wilgus A and Slawson DC: Diagnosis and management of endometriosis. Am Fam Physician. 74:594–600. 2006.PubMed/NCBI
30	Vercellini P, Vigano P, Somigliana E and Fedele L: Endometriosis: Pathogenesis and treatment. Nat Rev Endocrinol. 10:261–275. 2014. View Article : Google Scholar : PubMed/NCBI
31	Schweppe KW: Current place of progestins in the treatment of endometriosis-related complaints. Gynecol Endocrinol. 6:22–28. 2001. View Article : Google Scholar
32	Ruiz MP, Huang Y, Hou JY, Tergas AI, Burke WM, Ananth CV, Neugut AI, Hershman DL and Wright JD: All-cause mortality in young women with endometrial cancer receiving progesterone therapy. Am J Obstet Gynecol. 217:669.e1–669.e13. 2017. View Article : Google Scholar
33	Xie M, Zhu X, Liu Z, Shrubsole M, Varma V, Mayer IA, Dai Q, Chen Q and You S: Membrane progesterone receptor alpha as a potential prognostic biomarker for breast cancer survival: A retrospective study. PLoS One. 7:e351982012. View Article : Google Scholar : PubMed/NCBI
34	Thomas P: Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol. 29:292–312. 2008. View Article : Google Scholar : PubMed/NCBI
35	Dressing GE and Thomas P: Identification of membrane progestin receptors in human breast cancer cell lines and biopsies and their potential involvement in breast cancer. Steroids. 72:111–116. 2007. View Article : Google Scholar : PubMed/NCBI
36	Sleiter N, Pang Y, Park C, Horton TH, Dong J, Thomas P and Levine JE: Progesterone receptor A (PRA) and PRB-independent effects of progesterone on gonadotropin-releasing hormone release. Endocrinology. 150:3833–3844. 2009. View Article : Google Scholar : PubMed/NCBI
37	Zhu Y, Rice CD, Pang Y, Pace M and Thomas P: Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes. Proc Natl Acad Sci USA. 100:2231–2236. 2003. View Article : Google Scholar : PubMed/NCBI
38	Piasecka D, Skladanowski AC, Kordek R, Romanska HM and Sadej R: Aspects of progesterone receptor (PR) activity regulation-impact on breast cancer progression. Postepy Biochem. 61:198–206. 2015.PubMed/NCBI
39	Jiang LP, He CY and Zhu ZT: Role of microRNA-21 in radiosensitivity in non-small cell lung cancer cells by targeting PDCD4 gene. Oncotarget. 8:23675–23689. 2017.PubMed/NCBI
40	Dorrello NV, Peschiaroli A, Guardavaccaro D, Colburn NH, Sherman NE and Pagano M: S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science. 314:467–471. 2006. View Article : Google Scholar : PubMed/NCBI