Hu Ke, Lai Yue, Zhou Jinfeng, Hu Chaolu, Guo Shushan, Zhang Hui, Wang Guanli, Zhang Qikai, Gao Xuejie, Wang Zhuning, Liu Yujie, Feng Qilin, Yi Hongfei, Peng Yu, Zhang Yifei, Wu Xiaosong, Cai Haiyan, Shi Jumei
Department of Hematology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Int J Biol Sci. 2025 Jan 1;21(1):233-250. doi: 10.7150/ijbs.101850. eCollection 2025.
Chemoresistance is an important factor in multiple myeloma (MM) relapse and overall survival. However, the mechanism underlying resistance remains unclear. In this study, we identified adenine nucleotide translocase 3 (ANT3) as a novel biomarker and therapeutic target for MM progression and resistance to the proteasome inhibitor bortezomib (BTZ). The oncogenic functions of ANT3 in MM were verified using MM sensitive/drug-resistant cells, bone marrow tissues from patients with MM, orthotopic MM model, and subcutaneous tumor model. ANT3 knockdown impaired MM cell proliferation owing to a lack of cellular ATP levels, causing cell cycle arrest in the G0/G1 phase. Moreover, our study showed that ANT3 leads to BTZ resistance by promoting mitophagy. Notably, ANT3-mediated mitophagy is independent of its biological function as an ADP/ATP translocase. Mechanistically, ANT3 interacts with mitochondrial inner and outer membrane transporters, including Timm22 and Tomm20, thus restricting PINK1 import to the inner membrane of mitochondria. In this case, PINK1 is stabilized in the outer membrane of the mitochondria and recruits Parkin, resulting in mitophagy. Furthermore, targeted intervention with ANT3 combined with BTZ limited the growth of BTZ-resistant myeloma . This study identified ANT3 as a novel biomarker and therapeutic target for MM.
化疗耐药是多发性骨髓瘤（MM）复发和总体生存的一个重要因素。然而，耐药的潜在机制仍不清楚。在本研究中，我们确定腺嘌呤核苷酸转运体3（ANT3）是MM进展和对蛋白酶体抑制剂硼替佐米（BTZ）耐药的一种新型生物标志物和治疗靶点。使用MM敏感/耐药细胞、MM患者的骨髓组织、原位MM模型和皮下肿瘤模型验证了ANT3在MM中的致癌功能。由于细胞ATP水平缺乏，ANT3敲低损害了MM细胞增殖，导致细胞周期停滞在G0/G1期。此外，我们的研究表明，ANT3通过促进线粒体自噬导致BTZ耐药。值得注意的是，ANT3介导的线粒体自噬与其作为ADP/ATP转运体的生物学功能无关。从机制上讲，ANT3与线粒体内外膜转运蛋白相互作用，包括Timm22和Tomm20，从而限制PINK1导入线粒体内膜。在这种情况下，PINK1在线粒体外膜稳定并募集Parkin，导致线粒体自噬。此外，对ANT3进行靶向干预并联合BTZ可限制BTZ耐药骨髓瘤的生长。本研究确定ANT3是MM的一种新型生物标志物和治疗靶点。
