Loss of Sirtuin 1 Alters the Secretome of Breast Cancer Cells by Impairing Lysosomal Integrity
Loss of Sirtuin 1 Alters the Secretome of Breast Cancer Cells by Impairing Lysosomal Integrity
复制标题
DOI：
10.1016/j.devcel.2019.03.011
复制
发表时间：
2019-05-06
影响因子：
11.8
通讯作者：
Antonyak, Marc A.
中科院分区：
文献类型：
--
作者：
Latifkar, Arash;Ling, Lu;Antonyak, Marc A.
NAD(+)依赖的脱乙酰酶Sirtuin1(SIRT1)在三阴性乳腺癌中下调。为了确定SIRT1表达减少影响某些侵袭性癌症相关过程的机制基础，我们研究了SIRT1耗尽乳腺癌细胞的后果。我们发现，降低SIRT1水平会降低液泡型H+ATPase(V-ATPase)的一个特定亚基的表达，该亚基负责适当的溶酶体酸化和蛋白质降解。溶酶体功能的这种损害导致针对溶酶体降解的多囊泡体(MVB)的数量减少，并导致更大的MVB在与质膜融合以释放其内容物之前。总而言之，这些发现有助于解释SIRT1的表达减少是如何通过扰乱溶酶体的功能并产生一个分泌体来促进乳腺癌细胞存活和侵袭的过程，该分泌体包括具有独特货物的外切体和降解细胞外基质的可溶性水解酶。
The NAD(+)-dependent deacetylase Sirtuin 1 (SIRT1) is down-regulated in triple-negative breast cancer. To determine the mechanistic basis by which reduced SIRT1 expression influences processes related to certain aggressive cancers, we examined the consequences of depleting breast cancer cells of SIRT1. We discovered that reducing SIRT1 levels decreased the expression of one particular subunit of the vacuolar-type H+ ATPase (V-ATPase), which is responsible for proper lysosomal acidification and protein degradation. This impairment in lysosomal function caused a reduction in the number of multi-vesicular bodies (MVBs) targeted for lysosomal degradation and resulted in larger MVBs prior to their fusing with the plasma membrane to release their contents. Collectively, these findings help explain how reduced SIRT1 expression, by disrupting lysosomal function and generating a secretome comprising exosomes with unique cargo and soluble hydrolases that degrade the extracellular matrix, can promote processes that increase breast-cancer-cell survival and invasion.