CD147 modulates androgen receptor activity through the Akt/Gsk-3β/β-catenin/AR pathway in prostate cancer cells

Fang,Fang; Qin,Yingxin; Hao,Feng; Li,Qiang; Zhang,Wei; Zhao,Chen; Chen,Shuang; Zhao,Liangzhong; Wang,Liguo; Cai,Jianhui

doi:10.3892/ol.2016.4684

CD147 modulates androgen receptor activity through the Akt/Gsk-3β/β-catenin/AR pathway in prostate cancer cells

Authors:
- Fang Fang
- Yingxin Qin
- Feng Hao
- Qiang Li
- Wei Zhang
- Chen Zhao
- Shuang Chen
- Liangzhong Zhao
- Liguo Wang
- Jianhui Cai
View Affiliations

Affiliations: Department of Immunology, Jilin Medical University, Jilin 132013, P.R. China, Department of Anesthesiology, Affiliated Hospital of Jilin Medical University, Jilin 132011, P.R. China, Department of Biochemistry, Jilin Medical University, Jilin 132013, P.R. China, Department of Urology Surgery, Affiliated Hospital of Jilin Medical University, Jilin 132011, P.R. China
Published online on: June 7, 2016 https://doi.org/10.3892/ol.2016.4684
Pages: 1124-1128

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

The androgen signaling pathway serves an important role in the development of prostate cancer. β-Catenin is an androgen receptor (AR) cofactor and augments AR signaling. Glycogen synthase kinase-3β (GSK-3β), a target of phosphorylated serine/threonine protein kinase B (p-Akt), regulates β-catenin stability. In addition, β-catenin, a coregulator of AR, physically interacts with AR and enhances AR‑mediated target gene transcription. The multifunctional glycoprotein cluster of differentiation (CD) 147 is highly expressed on the cell surface of the majority of cancer cells, and it promotes tumor invasion, metastasis and growth. In the present study, the molecular effects of CD147 on the Akt/GSK‑3β/β‑catenin/AR signaling network were investigated in LNCaP cells. Using short hairpin‑mediated RNA knockdown of CD147 in LNCaP cells, it was demonstrated that downregulation of CD147 resulted in inhibitory phosphorylation of GSK‑3β, and then promoted degeneration of β‑catenin and reduced nuclear accumulation of β-catenin. In addition, immunoprecipitation studies demonstrated that CD147 downregulation decreased the formation of a complex between β‑catenin and AR. It was shown that CD147 knockdown suppressed the expression of the AR target gene prostate-specific antigen and the growth of AR‑positive LNCaP cells. Furthermore, inhibition of PI3K/Akt with LY294002 augmented CD147-mediated function. The present study indicates that the PI3K/Akt pathway may facilitate CD147-mediated activation of the AR pathway.

View Figures

View References

1	Scher HI, Solo K, Valant J, Todd MB and Mehra M: Prevalence of prostate cancer clinical states and mortality in United States: Estimates using a dynamic progression model. Plos One. 10:e01394402015. View Article : Google Scholar : PubMed/NCBI
2	Lorente D and De Bono JS: Molecular alterations and emerging targets in castration resistant prostate cancer. Eur J Cancer. 50:753–764. 2014. View Article : Google Scholar : PubMed/NCBI
3	Koivisto P, Kononen J, Palmberg C, Tammela T, Hyytinen E, Isola J, Trapman J, Cleutjens K, Noordzij A, Visakorpi T and Kallioniemi OP: Androgen receptor gene amplification: A possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res. 57:314–319. 1997.PubMed/NCBI
4	Tilley WD, Buchanan G, Hickey TE and Bentel JM: Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence. Clin Cancer Res. 2:277–285. 1996.PubMed/NCBI
5	Gottlieb B, Beitel LK, Wu JH and Trifiro M: The androgen receptor gene mutations database (ARDB): 2004 update. Hum Mutat. 23:527–533. 2004. View Article : Google Scholar : PubMed/NCBI
6	Chmelar R, Buchanan G, Need EF, Tilley W and Greenberg NM: Androgen receptor coregulators and their involvement in the development and progression of prostate cancer. Int J Cancer. 120:719–733. 2007. View Article : Google Scholar : PubMed/NCBI
7	Wang G, Wang J and Sadar MD: Crosstalk between the androgen receptor and beta-catenin in castrate-resistant prostate cancer. Cancer Res. 68:9918–9927. 2008. View Article : Google Scholar : PubMed/NCBI
8	Heinlein CA and Chang C: Androgen receptor (AR) coregulators: An overview. Endocr Rev. 23:175–200. 2002. View Article : Google Scholar : PubMed/NCBI
9	Yang F, Li X, Sharma M, Sasaki CY, Longo DL, Lim B and Sun Z: Linking beta-catenin to androgen-signaling pathway. J Biol Chem. 277:11336–11344. 2002. View Article : Google Scholar : PubMed/NCBI
10	Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X and He X: Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 108:837–847. 2002. View Article : Google Scholar : PubMed/NCBI
11	Ishibashi Y, Matsumoto T, Niwa M, Suzuki Y, Omura N, Hanyu N, Nakada K, Yanaga K, Yamada K, Ohkawa K, et al: CD147 and matrix metalloproteinase-2 protein expression as significant prognostic factors in esophageal squamous cell carcinoma. Cancer. 101:1994–2000. 2004. View Article : Google Scholar : PubMed/NCBI
12	Wang L, Wu G, Yu L, Yuan J, Fang F, Zhai Z, Wang F and Wang H: Inhibition of CD147 expression reduces tumor cell invasion in human prostate cancer cell line via RNA interference. Cancer Biol Ther. 5:608–614. 2006. View Article : Google Scholar : PubMed/NCBI
13	Grass GD, Dai L, Qin Z, Parsons C and Toole BP: CD147: Regulator of hyaluronan signaling in invasiveness and chemoresistance. Adv Cancer Res. 123:351–373. 2014. View Article : Google Scholar : PubMed/NCBI
14	Szubert S, Szpurek D, Moszynski R, Nowicki M, Frankowski A, Sajdak S and Michalak S: Extracellular matrix metalloproteinase inducer (EMMPRIN) expression correlates positively with active angiogenesis and negatively with basic fibroblast growth factor expression in epithelial ovarian cancer. J Cancer Res Clin Oncol. 140:361–369. 2014. View Article : Google Scholar : PubMed/NCBI
15	Fang F and Wang L, Zhang S, Fang Q, Hao F, Sun Y, Zhao L, Chen S, Liao H and Wang L: CD147 modulates autophagy through the PI3K/Akt/mTOR pathway in human prostate cancer PC-3 cells. Oncol Lett. 9:1439–1443. 2015.PubMed/NCBI
16	Sidhu SS, Nawroth R, Retz M, Lemjabbar-Alaoui H, Dasari V and Basbaum C: EMMPRIN regulates the canonical Wnt/beta-catenin signaling pathway, a potential role in accelerating lung tumorigenesis. Oncoqene. 29:4145–4156. 2010.
17	McCubrey JA, Steelman LS, Bertrand FE, Davis NM, Abrams SL, Montalto G, D'Assore AB, Libra M, Nicoletti F, Maestro R, et al: Multifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: Opportunities for therapeutic intervention. Leukemia. 28:15–33. 2014. View Article : Google Scholar : PubMed/NCBI
18	Scher HI and Sawyers CL: Biology of progressive, castration-resistant prostate cancer: Directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 23:8253–8261. 2005. View Article : Google Scholar : PubMed/NCBI
19	Verras M and Sun Z: Roles and regulation of Wnt signaling and beta-catenin in prostate cancer. Cancer Lett. 237:22–32. 2006. View Article : Google Scholar : PubMed/NCBI
20	Wu G, Xu G, Schulman BA, Jeffrey PD, Harper JW and Pavletich NP: Mol Cell. 11:1445–1456. 2003. View Article : Google Scholar : PubMed/NCBI
21	Zhu Q, Youn H, Tang J, Tawfik O, Dennis K, Terranova PF, Du J, Raynal P, Thrasher JB and Li B: Phosphoinositide 3-OH kinase p85 alpha and p110 beta are essential for androgen receptor transactivation and tumor progression in prostate cancers. Oncogene. 27:4569–4579. 2008. View Article : Google Scholar : PubMed/NCBI
22	Takahashi-Yanaga F and Sasaguri T: Drug development targeting the glycogen synthase kinase-3beta (GSK-3beta)-mediated signal transduction pathway: Inhibitors of the Wnt/beta-catenin signaling pathway as novel anticancer drugs. J Pharmacol Sci. 109:179–183. 2009. View Article : Google Scholar : PubMed/NCBI