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.
Wei-Hsiang Kao  1 ,  Kun-Yuan Chiu  2 ,  Stella Chin-Shaw Tsai  3 ,  Chieh-Lin Jerry Teng  4 ,  Muhammet Oner  5 ,  Chih-Ho Lai  6 ,  Jer-Tsong Hsieh  7 ,  Chi-Chien Lin  8 ,  Hsin-Yi Wang  9 ,  Mei-Chih Chen  10 ,  Ho Lin  11
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 p21CIP1, 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.
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