癌细胞可利用溶酶体功能以促进肿瘤进展。即癌细胞通过自噬和巨胞饮作用循环营养物以促进细胞生长，并通过释放MMP和组织蛋白酶促进侵袭和转移。Sirtuins是NAD+依赖性去乙酰化酶，其参与细胞对应激的反应并调节染色质结构、基因转录、细胞代谢、DNA修复和细胞增殖。最著名的成员Sirtuin 1（SIRT1）经常在乳腺癌中下调。近日，来自康奈尔大学的研究人员鉴定了SIRT1的新型乳腺癌肿瘤抑制功能，报道了SIRT1的损失可损害溶酶体功能，导致促肿瘤发生外泌体和水解酶组织蛋白酶B的分泌增加。相关研究结果发表在Developmental Cell杂志上。
该研究证明SIRT1的缺失增加了乳腺癌细胞中多泡体（MVB）的大小。这是由于溶酶体功能失调造成，其本该减少自噬作用和清除MVBs。MVB与质膜融合，释放外泌体，并且SIRT1缺陷细胞不仅增强了外泌体分泌，而且还有不同的外泌体蛋白质成分。总的来说，这些发现有助于解释通过破坏溶酶体功能并产生外泌体来降低SIRT1的表达，外泌体包含具有降解细胞外基质的可溶性水解酶，从而促进提高乳腺癌细胞存活和侵袭的过程。此外，从SIRT1缺失细胞释放的外泌体富含泛素化蛋白，进一步支持SIRT1功能将MVB重定向至质膜，而不是自噬体用于溶酶体降解。自噬相关蛋白ATG12-ATG3与Alix相互作用以控制基础自噬、晚期内体功能和外泌体的分泌。该研究首次证明受损的溶酶体改变了MVB的命运，为外泌体生物发生机制的研究提供了新思路，并开启了关于外泌体成分包装调控和外泌体对肿瘤微环境中受体细胞的影响的新见解。
推荐阅读原文：
Loss of Sirtuin 1 Alters the Secretome of Breast Cancer Cells by Impairing Lysosomal Integrity.
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.
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