Nauman Mirielle C, Won Jong Hoon, Petiwala Sakina M, Vemu Bhaskar, Lee Hyun, Sverdlov Maria, Johnson Jeremy J
Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
Cancers (Basel). 2023 Apr 1;15(7):2118. doi: 10.3390/cancers15072118.
A major limitation of current prostate cancer pharmacotherapy approaches is the inability of these compounds to target androgen receptor variants or mutants that develop during prostate cancer progression. The demand for novel therapeutics to prevent, slow, and treat prostate cancer is significant because FDA approved anti-androgens are associated with adverse events and can eventually drive drug-resistant prostate cancer. This study evaluated α-mangostin for its novel ability to degrade the androgen receptor and androgen receptor variants. α-Mangostin is one of more than 70 isoprenylated xanthones isolated from that we have been evaluating for their anticancer potential. Prostate cancer cells treated with α-mangostin exhibited decreased levels of wild-type and mutated androgen receptors. Immunoblot, immunoprecipitation, and transfection experiments demonstrated that the androgen receptor was ubiquitinated and subsequently degraded via the proteasome, which we hypothesize occurs with the assistance of BiP, an ER chaperone protein that we have shown to associate with the androgen receptor. We also evaluated α-mangostin for its antitumor activity and promotion of androgen receptor degradation in vivo. In summary, our study demonstrates that androgen receptor degradation occurs through the novel activation of BiP and suggests a new therapeutic approach for prostate cancer.
当前前列腺癌药物治疗方法的一个主要局限性是，这些化合物无法靶向前列腺癌进展过程中出现的雄激素受体变体或突变体。由于美国食品药品监督管理局（FDA）批准的抗雄激素药物会引发不良事件，并最终导致耐药性前列腺癌，因此对预防、延缓和治疗前列腺癌的新型疗法的需求十分巨大。本研究评估了α-山竹素降解雄激素受体及雄激素受体变体的新能力。α-山竹素是我们一直在评估其抗癌潜力的70多种异戊烯基氧杂蒽酮之一。用α-山竹素处理的前列腺癌细胞显示出野生型和突变型雄激素受体水平降低。免疫印迹、免疫沉淀和转染实验表明，雄激素受体被泛素化，随后通过蛋白酶体降解，我们推测这一过程是在内质网伴侣蛋白BiP的协助下发生的，我们已证明BiP与雄激素受体相关。我们还评估了α-山竹素在体内的抗肿瘤活性以及促进雄激素受体降解的能力。总之，我们的研究表明，雄激素受体降解是通过BiP的新激活而发生的，并为前列腺癌提出了一种新的治疗方法。
