TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells, but not in normal cells; as such, it is a promising therapeutic agent. However, therapeutic resistance limits its clinical use in many malignancies, including prostate cancer. Strategies to sensitize cancer cells to TRAIL are urgently needed. We demonstrate here that small-molecule tetrandrine (TET) potentially sensitizes previously resistant (LNCaP and C4-2B cells) and mildly sensitive (PC3 cells) prostate cancer cells to TRAIL-induced apoptosis, and they do so by upregulating mRNA expression and protein levels of death receptors Apo Trail R1 (DR4) and Apo Trail R2 (DR5). Using shRNA knockdown, we show critical requirement of DR4 and DR5 in sensitization of prostate cancer cells to TRAIL. We show that double knockdown of DR4 and DR5 abrogated the apoptotic effects of TET and TRAIL. We also demonstrate that TET-induced DR4 and DR5 expression is independent of p53 status. Given that loss of p53 is associated with progression of prostate cancer to CRPC and NEPC, our results show that TET, by acting as a TRAIL-sensitizing agent in prostate cancer, could serve as a potential therapeutic agent in CRPC and NEPC, for which there is no cure to date. Mol Cancer Ther; 17(6); 1217–28. ©2018 AACR.

中文翻译：

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粉防己碱 (TET) 诱导死亡受体：Apo Trail R1 (DR4) 和 Apo Trail R2 (DR5) 并使前列腺癌细胞对 TRAIL 诱导的细胞凋亡敏感

TNF 相关凋亡诱导配体 (TRAIL) 选择性诱导癌细胞凋亡，但不诱导正常细胞凋亡；因此，它是一种很有前途的治疗剂。然而，治疗耐药性限制了它在许多恶性肿瘤（包括前列腺癌）中的临床应用。迫切需要使癌细胞对 TRAIL 敏感的策略。我们在此证明，小分子粉防己碱 (TET) 可能使先前耐药（LNCaP 和 C4-2B 细胞）和轻度敏感（PC3 细胞）的前列腺癌细胞对 TRAIL 诱导的细胞凋亡敏感，并且它们通过上调 mRNA 表达和蛋白质水平来实现死亡受体 Apo Trail R1 (DR4) 和 Apo Trail R2 (DR5)。使用 shRNA 敲低，我们显示了 DR4 和 DR5 在前列腺癌细胞对 TRAIL 的敏感性中的关键要求。我们表明 DR4 和 DR5 的双重敲低消除了 TET 和 TRAIL 的凋亡作用。我们还证明 TET 诱导的 DR4 和 DR5 表达与 p53 状态无关。鉴于 p53 的丢失与前列腺癌进展为 CRPC 和 NEPC 有关，我们的结果表明，TET 通过在前列腺癌中充当 TRAIL 增敏剂，可以作为 CRPC 和 NEPC 的潜在治疗剂，为此迄今为止无法治愈。Mol 癌症疗法；17(6); 1217-28。©2018 AACR。可以作为 CRPC 和 NEPC 的潜在治疗剂，目前尚无治愈方法。Mol 癌症疗法；17(6); 1217-28。©2018 AACR。可以作为 CRPC 和 NEPC 的潜在治疗剂，目前尚无治愈方法。Mol 癌症疗法；17(6); 1217-28。©2018 AACR。