Tetrandrine (TET) Induces Death Receptors Apo Trail R1 (DR4) and Apo Trail R2 (DR5) and Sensitizes Prostate Cancer Cells to TRAIL-Induced Apoptosis.
Tetrandrine (TET) Induces Death Receptors Apo Trail R1 (DR4) and Apo Trail R2 (DR5) and Sensitizes Prostate Cancer Cells to TRAIL-Induced Apoptosis.
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DOI：
10.1158/1535-7163.mct-17-1157
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发表时间：
2018-06
影响因子：
5.7
通讯作者：
Koul, Hari K.
中科院分区：
文献类型：
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作者：
Shishodia, Gauri;Koul, Sweaty;Dong, Qin;Koul, Hari K.
肿瘤坏死因子相关的凋亡诱导配体(TRAIL)选择性地诱导癌细胞的凋亡，但不能诱导正常细胞的凋亡，因此是一种很有前途的治疗药物。然而，治疗耐药性限制了其在包括前列腺癌(PCa)在内的许多恶性肿瘤中的临床应用。迫切需要使癌细胞对TRAIL敏感的策略。我们在这里证明了小分子粉防己碱(Tet)潜在地使先前耐药(LNCaP和C4-2B细胞)和中等敏感(PC3细胞)的PCa细胞对TRAIL诱导的凋亡敏感，并且它们通过上调死亡受体Apo Trail R1(DR4)和Apo Trail R2(DR5)的mRNA表达和蛋白水平来做到这一点。利用shRNA敲除技术，我们证明了DR4和DR5在PCa细胞对TRAIL的敏化过程中的关键需求。我们发现双敲除DR4和DR5可阻断Tet和TRAIL的细胞凋亡作用。我们还证明了Tet诱导的DR4和DR5的表达与P53的状态无关。鉴于P53的缺失与PCa向CRPC和NEPC的进展有关，我们的结果表明，Tet作为TRAIL增敏剂在PCa中可能成为CRPC和NEPC的潜在治疗剂，目前尚无治愈方法。
TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells, but not in normal cells, as such is a promising therapeutic agent. However, therapeutic resistance limits its clinical use in many malignancies including prostate cancer (PCa). 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) PCa cells to TRAIL-induced apoptosis, and they do so by up-regulating 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 PCa cells to TRAIL. We show that double knock down 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 PCa to CRPC and NEPC, our results show that TET by acting as a TRAIL sensitizing agent in PCa could serve as a potential therapeutic agent in CRPC and NEPC for which there is no cure to date.