PI3K/Akt inhibition promotes AR activity and prostate cancer cell proliferation through p35-CDK5 modulation

Wei-Hsiang Kao; Kun-Yuan Chiu; Stella Chin-Shaw Tsai; Chieh-Lin Jerry Teng; Muhammet Oner; Chih-Ho Lai; Jer-Tsong Hsieh; Chi-Chien Lin; Hsin-Yi Wang; Mei-Chih Chen; Ho Lin

doi:10.1016/j.bbadis.2024.167568

PI3K/Akt inhibition promotes AR activity and prostate cancer cell proliferation through p35-CDK5 modulation

Biochim Biophys Acta Mol Basis Dis. 2025 Feb;1871(2):167568. doi: 10.1016/j.bbadis.2024.167568. Epub 2024 Nov 12.

Authors

Affiliations

¹ Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan; Translational Cell Therapy Center, China Medical University Hospital, Taichung 40447, Taiwan. Electronic address: [email protected].
² Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
³ Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan; Superintendent Office, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan; College of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan.
⁴ Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan; Division of Hematology/Medical Oncology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan. Electronic address: [email protected].
⁵ Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan. Electronic address: [email protected].
⁶ Department of Microbiology and Immunology, Chang Gung University, Taoyuan 33302, Taiwan. Electronic address: [email protected].
⁷ Department of Urology, University of Texas Southwestern Medical Center, TX75390, USA. Electronic address: [email protected].
⁸ Institute of Biomedical Science, National Chung Hsing University, Taichung 40227, Taiwan.
⁹ Department of Nuclear Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan. Electronic address: [email protected].
¹⁰ Translational Cell Therapy Center, China Medical University Hospital, Taichung 40447, Taiwan. Electronic address: [email protected].
¹¹ Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan. Electronic address: [email protected].

PMID: 39536992
DOI: 10.1016/j.bbadis.2024.167568

Abstract

Aberrant PI3K/Akt activation is linked to prostate cancer (PCa) malignancy, while androgen receptor (AR) is critical in early-stage PCa development. Investigating the interaction between these pathways is crucial for PCa malignancy. Our previous study demonstrated that p35-CDK5 mediates post-translational modifications of AR, STAT3, and p21^CIP1, eventually promoting PCa cell growth. This study revealed the role of p35-CDK5 in between PI3K/Akt and AR by utilizing LNCaP and 22Rv1 cells. Through the TCGA database analysis, we observed a positive correlation between PTEN and p35 expression, implying a potential negative correlation between PI3K/Akt activation and p35-CDK5. Inhibiting PI3K/Akt with LY294002, Capivasertib (AZD5363), or using an inactive Akt mutant significantly increased p35 expression and subsequently enhanced AR stability and activation in PCa cells. On the other hand, CDK5-knockdown reversed these effects. The involvement of the β-catenin/Egr1-axis was observed in regulating PI3K/Akt inhibition and p35-CDK5 activation, implying a possible mechanistic connection. Importantly, CDK5 knockdown further reduced PI3K/Akt-inhibition-induced AR and cell viability maintenance, suggesting a compensatory role for CDK5-AR in maintaining cell viability under Akt inhibition. In conclusion, PI3K/Akt inhibition could trigger p35-CDK5-dependent AR activation and cell viability, highlighting p35-CDK5 as a critical link connecting PI3K/Akt inhibition to AR activation and pivotal in PCa cell resistance to PI3K/Akt blockade.

Keywords: AR; Cell viability; PI3K/Akt; Prostate cancer; p35-CDK5.

MeSH terms

Cell Line, Tumor
Cell Proliferation* / drug effects
Chromones / pharmacology
Cyclin-Dependent Kinase 5* / antagonists & inhibitors
Cyclin-Dependent Kinase 5* / genetics
Cyclin-Dependent Kinase 5* / metabolism
Gene Expression Regulation, Neoplastic / drug effects
Humans
Male
Morpholines / pharmacology
Phosphatidylinositol 3-Kinases* / metabolism
Phosphoinositide-3 Kinase Inhibitors / pharmacology
Prostatic Neoplasms* / drug therapy
Prostatic Neoplasms* / genetics
Prostatic Neoplasms* / metabolism
Prostatic Neoplasms* / pathology
Proto-Oncogene Proteins c-akt* / metabolism
Pyrimidines / pharmacology
Pyrroles
Receptors, Androgen* / genetics
Receptors, Androgen* / metabolism
Signal Transduction / drug effects

Substances

Proto-Oncogene Proteins c-akt
Receptors, Androgen
CDK5 protein, human
Phosphatidylinositol 3-Kinases
Cyclin-Dependent Kinase 5
capivasertib
AR protein, human
Morpholines
Chromones
Pyrimidines
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Phosphoinositide-3 Kinase Inhibitors
Pyrroles