Taxanes Sensitize Prostate Cancer Cells to TRAIL-Induced Apoptotic Synergy via Endoplasmic Reticulum Stress
Taxanes Sensitize Prostate Cancer Cells to TRAIL-Induced Apoptotic Synergy via Endoplasmic Reticulum Stress
复制标题
DOI：
10.1158/1535-7163.mct-20-0495
复制
发表时间：
2021-05-01
影响因子：
5.7
通讯作者：
King, Michael R.
中科院分区：
文献类型：
--
作者：
Grayson, Korie A.;Hope, Jacob M.;King, Michael R.
多西他赛和卡巴他赛是转移性去势抵抗性前列腺癌（mCRPC）的指南化疗治疗，其中包括大多数前列腺癌死亡。肿瘤坏死因子相关凋亡诱导配体（TRAIL）是一种抗癌剂，对癌细胞具有选择性细胞毒性;然而，许多人类癌症对TRAIL具有抗性。在这项研究中，我们敏化雄激素非依赖性和TRAIL耐药的前列腺癌细胞的TRAIL介导的凋亡通过紫杉烷治疗，并检查敏化的机制。当用可溶性TRAIL、多西他赛或卡巴他赛单独处理时，DU 145和PC 3细胞显示细胞活力没有显著降低，表明两种细胞系分别对TRAIL和紫杉烷具有抗性。紫杉烷和TRAIL组合协同放大凋亡，强烈表明紫杉烷使前列腺癌细胞对TRAIL敏感。Jun N-末端激酶（JNK）抑制剂抑制经处理的细胞中的细胞凋亡并显著降低死亡受体表达，表明ER应激激活JNK通过上调DR 4/DR 5表达使PCa细胞对TRAIL诱导的细胞凋亡敏感。此外，C/EBP同源蛋白（CHOP）的抑制降低了两种细胞系中的TRAIL致敏性，表明ER应激相关的细胞凋亡部分由CHOP介导。细胞色素c敲低显示在PC 3细胞中的敏感性显著降低，但在cytochrome-deficient DU 145细胞中没有。使用计算模型来模拟用紫杉烷和TRAIL疗法处理的细胞的凋亡，如在体外实验中所证明的。紫杉烷类预处理可使细胞对TRAIL介导的凋亡诱导的凋亡敏感，这表明TRAIL与ER应激诱导剂的组合是逆转TRAIL抗性以治疗mCRPC的有前景的疗法。
Docetaxel and cabazitaxel are guideline-chemotherapy treatments for metastatic castration-resistant prostate cancer (mCRPC), which comprises the majority of prostate cancer deaths. TNF-related apoptosis inducing ligand (TRAIL) is an anticancer agent that is selectively cytotoxic to cancer cells; however, many human cancers are resistant to TRAIL. In this study, we sensitized androgen-independent and TRAIL-resistant prostate cancer cells to TRAIL-mediated apoptosis via taxane therapy and examined the mechanism of sensitization. DU145 and PC3 cells displayed no significant reduction in cell viability when treated with soluble TRAIL, docetaxel, or cabazitaxel alone indicating that both cell lines are resistant to TRAIL and taxanes individually. Taxane and TRAIL combination synergistically amplified apoptosis strongly suggesting that taxanes sensitize prostate cancer cells to TRAIL. A Jun N-terminal kinases (JNK) inhibitor inhibited apoptosis in treated cells and significantly reduced death receptor expression indicating JNK activation by ER stress sensitizes PCa cells to TRAIL-induced apoptosis by upregulating DR4/DR5 expression. In addition, suppression of C/EBP homologous protein (CHOP) reduced TRAIL sensitization in both cell lines indicating that ER stress-related apoptosis is mediated, in part, by CHOP. Cytochrome c knockdown showed a significant decrease in sensitivity in PC3 cells, but not in Bax-deficient DU145 cells. A computational model was used to simulate apoptosis for cells treated with taxane and TRAIL therapy as demonstrated in in vitro experiments. Pretreatment with taxanes sensitized cells to apoptosis induced by TRAIL-mediated apoptosis, demonstrating that combining TRAIL with ER stress inducers is a promising therapy to reverse TRAIL resistance to treat mCRPC.