The KDM5 Inhibitor PBIT Reduces Proliferation of Castration-resistant Prostate Cancer Cells Via Cell Cycle Arrest and the Induction of Senescence

Overview

Journal Exp Cell Res

Specialty Cell Biology

Date 2024 Mar 10

PMID 38462208

Authors

Tunde Smith

Tytianna White

Zhenbang Chen

LaMonica V Stewart

Affiliations

Soon will be listed here.

Abstract

The compound 2-4(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT) is an inhibitor of the KDM5 family of lysine-specific histone demethylases that has been suggested as a lead compound for cancer therapy. The goal of this study was to explore the effects of PBIT within human prostate cancers. Micromolar concentrations of PBIT altered proliferation of castration-sensitive LNCaP and castration-resistant C4-2B, LNCaP-MDV3100 and PC-3 human prostate cancer cell lines. We then characterized the mechanism underlying the anti-proliferative effects of PBIT within the C4-2B and PC-3 cell lines. Data from Cell Death ELISAs suggest that PBIT does not induce apoptosis within C4-2B or PC-3 cells. However, PBIT did increase the amount of senescence associated beta-galactosidase. PBIT also altered cell cycle progression and increased protein levels of the cell cycle protein p21. PC-3 and C4-2B cells express varying amounts of KDM5A, KDM5B, and KDM5C, the therapeutic targets of PBIT. siRNA-mediated knockdown studies suggest that inhibition of multiple KDM5 isoforms contribute to the anti-proliferative effect of PBIT. Furthermore, combination treatments involving PBIT and the PPARγ agonist 15-deoxy-Δ-12, 14 -prostaglandin J (15d-PGJ₂) also reduced PC-3 cell proliferation. Together, these data strongly suggest that PBIT significantly reduces the proliferation of prostate cancers via a mechanism that involves cell cycle arrest and senescence.

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