안드로겐-의존적 전립선암세포에서 신물질 MCS-C3의 안드로겐 민감성에 따른 농도특이적 세포사멸 유도기전

Abstract

Prostate cancer is the most frequently diagnosed and the second leading cause of male cancer death in the U.S. Androgen is essential for prostate development and homeostasis, and also for cancer progression. Therefore, the first-line treatment for the cancer is androgen deprivation therapy. Androgen exerts its biological effects by binding to androgen receptor (AR). Androgen regulates not only a series of androgen target genes, but also genes for cell cycle- and apoptosis-regulatory genes, such as p21CIP1, which induces cell cycle arrest in response to DNA damage and protects cancer cells against p53-mediated apoptosis. In the course of screening for novel modulators on apoptotic induction, we generated MCS-C3, a pyrrolo-pyrimidine derivative, which induced cell growth inhibition and apoptosis in time- and dose-dependent manner in non-prostate cancer PA-1 cells. In contrast, this compound didn�t show either growth inhibition or apoptotic induction in androgen-independent prostate cancer cells, such as C4-2 cells. However, MCS-C3 paradoxically induced apoptosis at specific drug concentration (5 �M) in androgen-dependent prostate cancer LNCaP and its subline cells (LNCaP-E9 and LNCaP-G4), while weakly inducing apoptosis at lower and higher drug concentrations. To investigate the molecular mechanisms underlying this paradoxical cellular response by MCS-C3, we performed Western blot and real-time PCR after treatment of 5 and 20 �M MCS-C3 with or without DHT, an AR activator, and Flutamide, an AR antagonist. Interestingly, paradoxical apoptotic induction of 5 �M of MCS-C3 is associated with dramatic up-regulation of p53-independent, AR-dependent p21CIP1. The responsibility to the compound was different among LNCaP and its sublines, which were matched to the induction of p21 gene by MCS-C3 not to their sensitivity to androgen for survival. Androgen, in general, up-regulation of p21CIP1 gene is stimulating prostate cancer proliferation. However, in contrast, we conclude that up-regulation of p21 by 5 �M of MCS-C3, which is p53-independent and AR-dependent, plays pivotal role in the cellular signaling pathways that control apoptosis in androgen-dependent prostate cancer cells differing in sensitivity to androgens, such as LNCaP, LNCaP�E9 and LNCaP-G4 cells.