Targeting IKKε in Androgen-Independent Prostate Cancer Causes Phenotypic Senescence and Genomic Instability.

Abstract

Advanced prostate cancer will often progress to a lethal, castration-resistant state. We previously demonstrated that IKKε expression correlated with the aggressiveness of prostate cancer disease. Here, we address the potential of IKKε as a therapeutic target in prostate cancer. We examined cell fate decisions (proliferation, cell death, and senescence) in IKKε-depleted PC-3 cells, which exhibited delayed cell proliferation and a senescent phenotype, but did not undergo cell death. Using IKKε/TBK1 inhibitors, BX795 and Amlexanox, we measured their effects on cell fate decisions in androgen-sensitive prostate cancer and androgen-independent prostate cancer cell lines. Cell-cycle analyses revealed a G2-M cell-cycle arrest and a higher proportion of cells with 8N DNA content in androgen-independent prostate cancer cells only. Androgen-independent prostate cancer cells also displayed increased senescence-associated (SA)-β-galactosidase activity; increased γH2AX foci; genomic instability; and altered p15, p16, and p21 expression. In our mouse model, IKKε inhibitors also decreased tumor growth of androgen-independent prostate cancer xenografts but not 22Rv1 androgen-sensitive prostate cancer xenografts. Our study suggests that targeting IKKε with BX795 or Amlexanox in androgen-independent prostate cancer cells induces a senescence phenotype and demonstrates in vivo antitumor activity. These results strengthen the potential of exploiting IKKε as a therapeutic target.

• Authors: Sophie Gilbert, Benjamin Péant, Nicolas Malaquin, Véronique Tu, Hubert Fleury, Kim Leclerc-Desaulniers, Francis Rodier, Anne-Marie Mes-Masson, Fred Saad
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 21 Issue 3 Pg. 407-418 (03 01 2022) ISSN: 1538-8514 [Electronic] United States
• PMID: 34965959 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Androgens
• I-kappa B Kinase

Topics

• Androgens (metabolism)
• Animals
• Cell Line, Tumor
• Cell Proliferation
• Cellular Senescence (genetics)
• Genomic Instability
• Humans
• I-kappa B Kinase (genetics, metabolism)
• Male
• Mice
• Phenotype
• Prostatic Neoplasms (drug therapy, genetics, metabolism)