Role of phosphatidylinositol-3-kinase/protein kinase B signaling in androgen-independent prostate cancer progression

Abstract

Prostate cancer (PCa) is a leading cause of cancer-related deaths in males. Over time, many patients develop castration-resistant PCa, which is associated with a poor prognosis. Although the mechanisms underlying treatment failure remain unclear, the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway plays an important role in the failure of castration treatment. This study aims to explore the role of the PI3K/Akt pathway in androgen-independent PCa (AIPC) using clinical data and validate the cellular-level experimental findings by analyzing the expression of androgen receptor (AR), PI3K, and Akt in PCa. Patients were classified into two groups: AIPC (n = 38) and androgen-dependent PCa (ADPC) (n = 38). The expression levels of AR, PI3K, or Akt were evaluated through immunohistochemical analysis. Statistical analyses were performed to examine the correlations among AR, PI3K, and Akt. Significant differences (p < 0.01) were observed between groups with prostate-specific antigen levels ≤20 ng/mL and >20 ng/mL. The Gleason score in the AIPC group was significantly higher than in the ADPC group (p < 0.01). Positive expression of AR, PI3K, and phosphorylated Akt was observed in the nucleus, cytoplasm, and both the cytoplasm and nucleus, respectively. In AIPC patients, AR, PI3K, and Akt were positively correlated, confirming the clinical relevance of PI3K and Akt in the progression of AIPC. These findings suggest that the PI3K/Akt pathway serves as a potential regulator of AR activation and plays a crucial role in the progression of AIPC.

Keywords

Androgen receptor / Phosphatidylinositol-3-kinase / Protein kinase B / Androgen-independent prostate cancer

References

[1] Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3):229-263. doi: 10.3322/caac.21834

[2] Huggins C, Hodges CV. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol. 2002; 168(1):9-12. doi: 10.1016/S0022-5347(05)64820-3

[3] Epstein JI, Egevad L, Amin MB, et al. The 2014 international society of urological pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma: Definition of grading patterns and proposal for a new grading system. Am J Surg Pathol. 2016; 40(2):244-252. doi: 10.1097/PAS.0000000000000530

[4] Culig Z, Klocker H, Bartsch G, Steiner H, Hobisch A.Androgen receptors in prostate cancer. J Urol. 2003; 170(4 Pt 1):1363-1369. doi: 10.1097/01.ju.0000075099.20662.7f

[5] Hobisch A, Culig Z, Radmayr C, Bartsch G, Klocker H, Hittmair A. Distant metastases from prostatic carcinoma express androgen receptor protein. Cancer Res. 1995; 55(14):3068-3072.

[6] Attard G, Swennenhuis JF, Olmos D, et al. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res. 2009; 69(7):2912-2918. doi: 10.1158/0008-5472.CAN-08-3667

[7] Manning BD, Toker A. AKT/PKB signaling: Navigating the network. Cell. 2017; 169(3):381-405. doi: 10.1016/j.cell.2017.04.001

[8] Glaviano A, Foo AS, Lam HY, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 2023; 22(1):138. doi: 10.1186/s12943-023-01827-6

[9] Wang R, Qu Z, Lv Y, et al. Important roles of PI3K/AKT signaling pathway and relevant inhibitors in prostate cancer progression. Cancer Med. 2024; 13(21):e70354. doi: 10.1002/cam4.70354

[10] Chen CY, Chen J, He L, Stiles BL. PTEN: Tumor suppressor and metabolic regulator. Front Endocrinol (Lausanne). 2018; 9:338. doi: 10.3389/fendo.2018.00338

[11] Murillo H, Huang H, Schmidt LJ, Smith DI, Tindall DJ. Role of PI3K signaling in survival and progression of LNCaP prostate cancer cells to the androgen refractory state. Endocrinology. 2001; 142(11):4795-4805. doi: 10.1210/endo.142.11.8467

[12] Malik SN, Brattain M, Ghosh PM, et al. Immunohistochemical demonstration of phospho-akt in high Gleason grade prostate cancer. Clin Cancer Res. 2002; 8(4):1168-1171.

[13] Pungsrinont T, Kallenbach J, Baniahmad A. Role of PI3K-AKT-mTOR pathway as a pro-survival signaling and resistance-mediating mechanism to therapy of prostate cancer. Int J Mol Sci. 2021; 22(20):11088. doi: 10.3390/ijms222011088

[14] Mohler JL, Armstrong AJ, Bahnson RR, et al. Prostate cancer, version 3.2012: featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2012; 10(9):1081-1087. doi: 10.6004/jnccn.2012.0114

[15] Aurilio G, Cimadamore A, Mazzucchelli R, et al. Androgen receptor signaling pathway in prostate cancer: From genetics to clinical applications. Cells. 2020; 9(12):2653. doi: 10.3390/cells9122653

[16] Chandrasekar T, Yang JC, Gao AC, Evans CP. Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Transl Androl Urol. 2015; 4(3):365-380. doi: 10.3978/j.issn.2223-4683.2015.05.02

[17] Huang Y, Jiang X, Liang X, Jiang G. Molecular and cellular mechanisms of castration resistant prostate cancer. Oncol Lett. 2018; 15(5):6063-6076. doi: 10.3892/ol.2018.8123

[18] Bitting RL, Armstrong AJ. Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer. Endocr Relat Cancer. 2013; 20(3):R83-R99. doi: 10.1530/ERC-12-0394

[19] Mulholland DJ, Tran LM, Li Y, et al. Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell. 2011; 19(6):792-804. doi: 10.1016/j.ccr.2011.05.006

[20] Carver BS, Chapinski C, Wongvipat J, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell. 2011; 19(5):575-586. doi: 10.1016/j.ccr.2011.04.008

[21] Edlind MP, Hsieh AC. PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance. Asian J Androl. 2014; 16(3):378-386. doi: 10.4103/1008-682X.122876

[22] Liang F, Yue J, Wang J, et al. GPCR48/LGR4 promotes tumorigenesis of prostate cancer via PI3K/Akt signaling pathway. Med Oncol. 2015; 32(3):49. doi: 10.1007s12032-015-0486-1

[23] Lu Q, Liu Z, Li Z, et al. TIPE2 overexpression suppresses the proliferation, migration, and invasion in prostate cancer cells by inhibiting PI3K/Akt signaling pathway. Oncol Res. 2016; 24(5):305-313. doi: 10.3727/096504016X14666990347437

[24] Lin HK, Yeh S, Kang HY, Chang C. Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc Natl Acad Sci U S A. 2001; 98(13):7200-7205. doi: 10.1073/pnas.121173298

[25] Manin M, Baron S, Goossens K, et al. Androgen receptor expression is regulated by the phosphoinositide 3-kinase/Akt pathway in normal and tumoral epithelial cells. Biochem J. 2002; 366(Pt 3):729-736. doi: 10.1042/BJ20020585

[26] Sharma M, Chuang WW, Sun Z. Phosphatidylinositol 3- kinase/Akt stimulates androgen pathway through GSK3beta inhibition and nuclear beta-catenin accumulation. J Biol Chem. 2002; 277(34):30935-30941. doi: 10.1074/jbc.M201919200

[27] Ehsani M, David FO, Baniahmad A. Androgen receptor-dependent mechanisms mediating drug resistance in prostate cancer. Cancers (Basel). 2021; 13(7):1534. doi: 10.3390/cancers13071534