Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction.
Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction.
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DOI：
10.7554/elife.82860
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发表时间：
2022-11-21
期刊：
影响因子：
7.7
通讯作者：
Rutter J
中科院分区：
文献类型：
--
作者：
Winter JM;Fresenius HL;Cunningham CN;Wei P;Keys HR;Berg J;Bott A;Yadav T;Ryan J;Sirohi D;Tripp SR;Barta P;Agarwal N;Letai A;Sabatini DM;Wohlever ML;Rutter J
肿瘤抑制基因PTEN是第二个最常见的癌症缺失基因。这种缺失通常包括染色体10 q23位点超出PTEN本身界限的部分，这经常破坏相邻基因。PTEN邻近基因的偶然丢失可能会造成脆弱性，可能会影响患者的结果基本或被利用治疗。在这里，我们描述了如何ATAD 1，这是相邻的，并经常与PTEN共同删除的损失，易受癌细胞的蛋白酶体功能障碍引发的细胞凋亡，并与癌症患者的生存率提高。ATAD 1直接特异性地从线粒体中提取促凋亡蛋白BIM并使其凋亡。缺乏ATAD 1的培养细胞和小鼠异种移植物对临床使用的蛋白酶体抑制剂过敏，其激活BIM并触发凋亡。这项工作进一步加深了我们对线粒体蛋白稳态的理解，并可能为数十万患有染色体10 q23缺失肿瘤的癌症患者带来新的治疗选择。癌细胞通常会丢失控制细胞分裂时间和方式的基因序列。然而，删除这些基因并不是一门精确的艺术，相邻的序列在这个过程中经常被删除。例如，肿瘤抑制基因PTEN（癌症中第二大缺失基因）的缺失通常涉及附近ATAD 1基因的去除。虽然成千上万的人类肿瘤完全缺乏ATAD 1，但出生时没有该基因功能版本的个体无法存活过幼儿期。肿瘤细胞如何科普没有ATAD 1的情况-这些应对策略能否成为新疗法的目标？Winter等人旨在通过在实验室中检查缺乏ATAD 1的各种癌细胞来回答这些问题。在正常情况下，这种基因编码的酶位于线粒体的表面，线粒体是能量产生所必需的细胞区室。在那里，它提取任何有缺陷的蛋白质，否则可能造成破坏并危及线粒体健康。实验表明，如果没有ATAD 1，癌细胞开始更加依赖于一种替代机制来去除有害蛋白质：该过程以MARCH 5为中心，这种酶标记需要去除的分子，以便细胞可以回收它们。阻断MARCH 5通路的药物已经存在，但到目前为止，它们已被用于治疗其他类型的肿瘤。Winter等人表明，使用这些化合物会导致ATAD 1缺陷癌细胞的死亡，包括在小鼠中生长的人类肿瘤。总的来说，这项工作表明，失去ATAD 1的癌细胞更容易受到MARCH 5介导的蛋白质去除途径的破坏，包括通过现有的药物。如果通过进一步的翻译工作得到证实，这些发现可能会产生重要的临床影响，因为PTEN和ATAD 1在癌症中一起丢失的频率很高。
The tumor suppressor gene PTEN is the second most commonly deleted gene in cancer. Such deletions often include portions of the chromosome 10q23 locus beyond the bounds of PTEN itself, which frequently disrupts adjacent genes. Coincidental loss of PTEN-adjacent genes might impose vulnerabilities that could either affect patient outcome basally or be exploited therapeutically. Here, we describe how the loss of ATAD1, which is adjacent to and frequently co-deleted with PTEN, predisposes cancer cells to apoptosis triggered by proteasome dysfunction and correlates with improved survival in cancer patients. ATAD1 directly and specifically extracts the pro-apoptotic protein BIM from mitochondria to inactivate it. Cultured cells and mouse xenografts lacking ATAD1 are hypersensitive to clinically used proteasome inhibitors, which activate BIM and trigger apoptosis. This work furthers our understanding of mitochondrial protein homeostasis and could lead to new therapeutic options for the hundreds of thousands of cancer patients who have tumors with chromosome 10q23 deletion. Cancer cells have often lost genetic sequences that control when and how cell division takes place. Deleting these genes, however, is not an exact art, and neighboring sequences regularly get removed in the process. For example, the loss of the tumor suppressor gene PTEN, the second most deleted gene in cancer, frequently involves the removal of the nearby ATAD1 gene. While hundreds of thousands of human tumors completely lack ATAD1, individuals born without a functional version of this gene do not survive past early childhood. How can tumor cells cope without ATAD1 – and could these coping strategies become the target for new therapies? Winter et al. aimed to answer these questions by examining a variety of cancer cells lacking ATAD1 in the laboratory. Under normal circumstances, the enzyme that this gene codes for sits at the surface of mitochondria, the cellular compartments essential for energy production. There, it extracts any faulty, defective proteins that may otherwise cause havoc and endanger mitochondrial health. Experiments revealed that without ATAD1, cancer cells started to rely more heavily on an alternative mechanism to remove harmful proteins: the process centers on MARCH5, an enzyme which tags molecules that require removal so the cell can recycle them. Drugs that block the pathway involving MARCH5 already exist, but they have so far been employed to treat other types of tumors. Winter et al. showed that using these compounds led to the death of cancerous ATAD1-deficient cells, including in human tumors grown in mice. Overall, this work demonstrates that cancer cells which have lost ATAD1 become more vulnerable to disruptions in the protein removal pathway mediated by MARCH5, including via already existing drugs. If confirmed by further translational work, these findings could have important clinical impact given how frequently PTEN and ATAD1 are lost together in cancer.
影响因子：
3.7
作者：
Dai C;Liang D;Li H;Sasaki M;Dawson TM;Dawson VL
通讯作者：
Dawson VL