Hartman Mariusz L
Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215, Lodz, Poland.
Cell Death Dis. 2024 Dec 18;15(12):917. doi: 10.1038/s41419-024-07307-z.
Apoptosis-regulating proteins from the B-cell lymphoma-2 (BCL-2) family are of continued interest as they represent promising targets for anti-cancer therapies. Myeloid cell leukemia-1 (MCL-1), which usually refers to the long isoform (MCL-1L) is frequently overexpressed in various types of cancer. However, MCL1 pre-mRNA can also undergo alternative splicing through exon skipping to yield the short isoform, MCL-1S. Regarding its structure and function, MCL-1S corresponds to BCL-2 homology domain 3 (BH3)-only pro-apoptotic proteins in contrast to the pro-survival role of MCL-1L. As cancer cells are usually characterized by the high MCL-1L:MCL-1S ratio, several studies revealed that overexpression of MCL-1S may constitute a new therapeutic approach in cancer and presumably overcome resistance to currently available drugs. Switching the balance towards high levels of MCL-1S is feasible by using inhibitors of alternative splicing-regulating proteins and strategies directly interfering with MCL1 pre-mRNA. Additionally, several compounds were shown to increase MCL-1S levels through unelucidated mechanisms, while diversely affecting the level of MCL-1L isoform. These mechanisms require detailed clarification as the balance between the long and short variants of MCL-1 can also contribute to mitochondrial hyperpolarization. In this respect, the role of MCL-1S in the regulation of apoptosis-unrelated events of the mitochondria physiology, including mitochondria fission and fusion also remains to be determined. In this review, the structure and function of MCL-1S isoform, and MCL-1S-targeting approaches are discussed.
来自B细胞淋巴瘤-2（BCL-2）家族的凋亡调节蛋白一直备受关注，因为它们是抗癌治疗的有前景的靶点。髓系细胞白血病-1（MCL-1），通常指长异构体（MCL-1L），在各种类型的癌症中经常过度表达。然而，MCL1前体mRNA也可以通过外显子跳跃进行可变剪接，产生短异构体MCL-1S。就其结构和功能而言，与MCL-1L的促生存作用相反，MCL-1S对应于仅含BCL-2同源结构域3（BH3）的促凋亡蛋白。由于癌细胞通常以高MCL-1L:MCL-1S比率为特征，多项研究表明，MCL-1S的过度表达可能构成癌症治疗的新方法，并可能克服对现有药物的耐药性。通过使用可变剪接调节蛋白抑制剂和直接干扰MCL1前体mRNA的策略，将平衡转向高水平的MCL-1S是可行的。此外，几种化合物通过未阐明的机制显示可增加MCL-1S水平，同时对MCL-1L异构体的水平有不同影响。由于MCL-1的长、短变体之间的平衡也可能导致线粒体超极化，这些机制需要详细阐明。在这方面，MCL-1S在线粒体生理学凋亡无关事件（包括线粒体分裂和融合）调节中的作用也有待确定。在这篇综述中，将讨论MCL-1S异构体的结构和功能以及靶向MCL-1S的方法。
