Background/Objectives: Metastatic prostate cancer (PCa) is the leading cause of cancer-related deaths and a major contributor to cancer mortality in men. Most patients with metastatic PCa eventually develop metastatic castration-resistant prostate cancer (mCRPC), characterized by resistance to treatment with androgen-deprivation therapy, and often later the development of resistance to other types of agents. MAGMAS, a 13.8 kDa mitochondrial-associated protein, facilitates the import of nuclear-encoded proteins into the mitochondrial matrix. Overexpression of MAGMAS has been observed in several aggressive cancers, including breast, glioblastoma, and prostate cancer. When overexpressed, MAGMAS acts as a cytoprotective protein by scavenging reactive oxygen species (ROS), maintaining ROS levels that support cell proliferation while avoiding the induction of apoptosis. This study investigates the role of MAGMAS in therapy resistance in PCa cells. Methods/Results: Quantitative immunoblotting revealed that MAGMAS is endogenously upregulated in docetaxel-resistant (DR) PCa cell lines compared to their docetaxel-sensitive parental counterparts. While MAGMAS depletion alone did not affect the survival of DR cells, it significantly sensitized them to docetaxel (DTX), as indicated by a marked reduction in clonogenic potential. Additionally, transient knockdown of MAGMAS in these resistant cells significantly decreased the levels of ABCB1 protein. Consistent with these findings, sub-therapeutic inhibition of MAGMAS using the novel BT#9 inhibitor, in combination with increasing concentrations of DTX, enhanced the sensitivity of DR cells to DTX, as demonstrated by proliferation and clonogenic assays. Lastly, RNA tumor expression predicts overall survival (OS). Conclusions: These results implicate MAGMAS in PCa chemoresistance and suggest that targeting this protein could provide a novel therapeutic strategy for treating DR tumors.
背景/目的：转移性前列腺癌是癌症相关死亡的主要原因，也是男性癌症死亡率的主要贡献者。大多数转移性前列腺癌患者最终会发展为转移性去势抵抗性前列腺癌，其特征是对雄激素剥夺疗法产生耐药性，且后期常对其他类型药物也产生耐药性。MAGMAS是一种13.8 kDa的线粒体相关蛋白，能促进核编码蛋白向线粒体基质的转运。在多种侵袭性癌症（包括乳腺癌、胶质母细胞瘤和前列腺癌）中均观察到MAGMAS的过表达。过表达的MAGMAS通过清除活性氧发挥细胞保护作用，维持支持细胞增殖的活性氧水平，同时避免诱导细胞凋亡。本研究探讨MAGMAS在前列腺癌细胞治疗耐药中的作用。方法/结果：定量免疫印迹分析显示，与多西他赛敏感亲本细胞系相比，多西他赛耐药前列腺癌细胞系中MAGMAS内源性表达上调。虽然单独敲低MAGMAS不影响耐药细胞的存活，但能显著增强其对多西他赛的敏感性，表现为克隆形成能力显著降低。此外，在这些耐药细胞中瞬时敲低MAGMAS可显著降低ABCB1蛋白水平。与这些发现一致的是，使用新型BT#9抑制剂对MAGMAS进行亚治疗剂量抑制，联合递增浓度的多西他赛，可增强耐药细胞对多西他赛的敏感性，增殖实验和克隆形成实验均证实了这一点。最后，肿瘤RNA表达水平可预测患者总生存期。结论：这些结果表明MAGMAS参与前列腺癌化疗耐药，提示靶向该蛋白可能为治疗多西他赛耐药肿瘤提供新的治疗策略。
肿瘤(癌症)患者之家