Estrogen stimulates the invasion of ovarian cancer cells via activation of the PI3K/AKT pathway and regulation of its downstream targets E‑cadherin and α‑actinin‑4

Lu,Zhiying; Zhang,Ying; Yan,Xiaohui; Chen,Yisong; Tao,Xiang; Wang,Jiajia; Jia,Nan; Lyu,Tianjiao; Wang,Junyan; Ding,Jingxin; Feng,Weiwei; Hua,Keqin

doi:10.3892/mmr.2014.2561

Estrogen stimulates the invasion of ovarian cancer cells via activation of the PI3K/AKT pathway and regulation of its downstream targets E‑cadherin and α‑actinin‑4

Authors:
- Zhiying Lu
- Ying Zhang
- Xiaohui Yan
- Yisong Chen
- Xiang Tao
- Jiajia Wang
- Nan Jia
- Tianjiao Lyu
- Junyan Wang
- Jingxin Ding
- Weiwei Feng
- Keqin Hua
View Affiliations

Affiliations: Department of Gynecology, The Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China, Department of Pathology, The Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China
Published online on: September 12, 2014 https://doi.org/10.3892/mmr.2014.2561
Pages: 2433-2440

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

Previous studies by our group revealed that the phosphoinositide 3‑kinase (PI3K)/AKT pathway was involved in estrogen‑induced metastasis in ovarian cancer cells. In the present study, the role and mechanism of estrogen‑induced invasion was further explored using a stable short hairpin RNA (shRNA) estrogen receptor α/β (ER α/β) SKOV3 cell line when ER α and ER β were knocked down by lentiviral infection. The effects of estrogen and LY294002, a PI3K inhibitor, on the invasion of shRNA ER α/β SKOV3 cells were evaluated in vitro and in vivo. 17‑β estradiol promoted cell invasion, activated phosphorylated AKT in a dose‑ and time‑dependent manner, decreased E‑cadherin and increased cytoplasmic α‑actinin‑4 expression. When the PI3K/AKT pathway was suppressed by LY294002, the effect of estrogen was attenuated. Estrogen stimulated the growth of shRNA ER α/β SKOV3 xenograft tumors in nude mice, whereas LY294002 inhibited the growth and antagonized the effect of estrogen. The results indicate that estrogen promotes the invasion of ovarian cancer cells via activation of the PI3K/AKT pathway, downregulation of E‑cadherin and upregulation of α‑actinin‑4 in an ER‑independent manner. Inhibiting the PI3K/AKT pathway may be a useful treatment for ovarian carcinoma.

View Figures

View References

1	Ding JX, Feng YJ, Yao LQ, Yu M, Jin HY and Yin LH: The reinforcement of invasion in epithelial ovarian cancer cells by 17 beta-estradiol is associated with upregulation of Snail. Gynecol Oncol. 103:623–630. 2006. View Article : Google Scholar : PubMed/NCBI
2	Hua K, Feng W, Cao Q, Zhou X, Lu X and Feng Y: Estrogen and progestin regulate metastasis through the PI3K/AKT pathway in human ovarian cancer. Int J Oncol. 33:959–967. 2008.PubMed/NCBI
3	Hua K, Din J, Cao Q, Feng W, Zhang Y, Yao L, Huang Y, Zhao Y and Feng Y: Estrogen and progestin regulate HIF-1alpha expression in ovarian cancer cell lines via the activation of Akt signaling transduction pathway. Oncol Rep. 21:893–898. 2009.PubMed/NCBI
4	Kong L, Schäfer G, Bu H, Zhang Y, Zhang Y and Klocker H: Lamin A/C protein is overexpressed in tissue-invading prostate cancer and promotes prostate cancer cell growth, migration and invasion through the PI3K/AKT/PTEN pathway. Carcinogenesis. 33:751–759. 2012. View Article : Google Scholar
5	Riggio M, Polo ML, Blaustein M, Colman-Lerner A, Lüthy I, Lanari C and Novaro V: PI3K/AKT pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer. Carcinogenesis. 33:509–518. 2012. View Article : Google Scholar : PubMed/NCBI
6	Huang XF and Chen JZ: Obesity, the PI3K/AKT signal pathway and colon cancer. Obes Rev. 10:610–616. 2009. View Article : Google Scholar : PubMed/NCBI
7	Cantley LC, Auger KR, Carpenter C, Duckworth B, Graziani A, Kapeller R and Soltoff S: Oncogenes and signal transduction. Cell. 64:281–302. 1991. View Article : Google Scholar
8	Cantley LC and Neel BG: New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA. 96:4240–4245. 1999. View Article : Google Scholar : PubMed/NCBI
9	Yip WK and Seow HF: Activation of phosphatidylinositol 3-kinase/AKT signaling by EGF downregulates membranous E-cadherin and β-catenin and enhances invasion in nasopharyngeal carcinoma cells. Cancer Lett. 318:162–172. 2012.PubMed/NCBI
10	Wang Y, Sheng Q, Spillman MA, Behbakht K and Gu H: Gab2 regulates the migratory behaviors and E-cadherin expression via activation of the PI3K pathway in ovarian cancer cells. Oncogene. 31:2512–2520. 2012. View Article : Google Scholar : PubMed/NCBI
11	Shibasaki F, Fukami K, Fukui Y and Takenawa T: Phosphatidylinositol 3-kinase binds to alpha-actinin through the p85 subunit. Biochem J. 302:551–557. 1994.PubMed/NCBI
12	Ding Z, Liang J, Lu Y, Yu Q, Songyang Z, Lin SY and Mills GB: A retrovirus-based protein complementation assay screen reveals functional AKT1-binding partners. Proc Natl Acad Sci USA. 103:15014–15019. 2006. View Article : Google Scholar : PubMed/NCBI
13	Koay MH, Crook M and Stewart CJ: Cyclin D1, E-cadherin and beta-catenin expression in FIGO Stage IA cervical squamous carcinoma: diagnostic value and evidence for epithelial-mesenchymal transition. Histopathology. 61:1125–1133. 2012. View Article : Google Scholar
14	Xiong H, Hong J, Du W, Lin YW, Ren LL, Wang YC, Su WY, Wang JL, Cui Y, Wang ZH and Fang JY: Roles of STAT3 and ZEB1 proteins in E-cadherin down-regulation and human colorectal cancer epithelial-mesenchymal transition. J Biol Chem. 287:5819–5832. 2012. View Article : Google Scholar : PubMed/NCBI
15	Lombaerts M, van Wezel T, Philippo K, Dierssen JW, Zimmerman RM, Oosting J, van Eijk R, Eilers PH, van de Water B, Cornelisse CJ and Cleton-Jansen AM: E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines. Br J Cancer. 94:661–671. 2006.
16	Gravdal K, Halvorsen OJ, Haukaas SA and Akslen LA: A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin Cancer Res. 13:7003–7011. 2007. View Article : Google Scholar
17	Lau MT, Klausen C and Leung PC: E-cadherin inhibits tumor cell growth by suppressing PI3K/AKT signaling via β-catenin-Egr1-mediated PTEN expression. Oncogene. 30:2753–2766. 2011.PubMed/NCBI
18	Cheng JC, Auersperg N and Leung PC: Inhibition of p53 induces invasion of serous borderline ovarian tumor cells by accentuating PI3K/Akt-mediated suppression of E-cadherin. Oncogene. 30:1020–1031. 2011. View Article : Google Scholar : PubMed/NCBI
19	Pearce ST and Jordan VC: The biological role of estrogen receptors alpha and beta in cancer. Crit Rev Oncol Hematol. 50:3–22. 2004. View Article : Google Scholar : PubMed/NCBI
20	Park SH, Cheung LW, Wong AS and Leung PC: Estrogen regulates Snail and Slug in the down-regulation of E-cadherin and induces metastatic potential of ovarian cancer cells through estrogen receptor alpha. Mol Endocrinol. 22:2085–2098. 2008. View Article : Google Scholar
21	Kohn EC and Liotta LA: Molecular insights into cancer invasion: strategies for prevention and intervention. Cancer Res. 55:1856–1862. 1995.PubMed/NCBI
22	Brustmann H and Naudé S: Expression of nm23 in normal, hyperplastic and neoplastic endometrial tissues. Pathol Res Pract. 195:829–834. 1999. View Article : Google Scholar : PubMed/NCBI
23	Chen XF, Zhang HT, Qi QY, Sun MM and Tao LY: Expression of E-cadherin and nm23 is associated with the clinicopathological factors of human non-small cell lung cancer in China. Lung Cancer. 48:69–76. 2005. View Article : Google Scholar : PubMed/NCBI
24	Ohta S, Lai EW, Pang AL, Brouwers FM, Chan WY, Eisenhofer G, de Krijger R, Ksinantova L, Breza J, Blazicek P, Kvetnansky R, Wesley RA and Pacak K: Downregulation of metastasis suppressor genes in malignant pheochromocytoma. Int J Cancer. 114:139–143. 2005. View Article : Google Scholar : PubMed/NCBI
25	Bellacosa A, de Feo D, Godwin AK, Bell DW, Cheng JQ, Altomare DA, Wan M, Dubeau L, Scambia G, Masciullo V, Ferrandina G, Benedetti Panici P, Mancuso S, Neri G and Testa JR: Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer. 64:280–285. 1995. View Article : Google Scholar : PubMed/NCBI
26	Yuan ZQ, Sun M, Feldman RI, Wang G, Ma X, Jiang C, Coppola D, Nicosia SV and Cheng JQ: Frequent activation of AKT2 and induction of apoptosis by inhibition of phosphoinositide-3-OH kinase/Akt pathway in human ovarian cancer. Oncogene. 19:2324–2330. 2000. View Article : Google Scholar : PubMed/NCBI
27	Altomare DA, Wang HQ, Skele KL, De Rienzo A, Klein-Szanto AJ, Godwin AK and Testa JR: AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene. 23:5853–5857. 2004. View Article : Google Scholar