Abstract 4506: Loss of SIRT1 alters the secretome of breast cancer cells by impairing lysosomal integrity

Sirtuin 1 (SIRT1) is an NAD-dependent deacetylase implicated in processes ranging from lifespan promotion to tumor suppression. To probe its role as a tumor suppressor, we knocked down SIRT1 in breast cancer cells. This resulted in the decreased expression of one of the subunits comprising the multi-subunit vacuolar-type H+ ATPase (V-ATPase), which is responsible for the acidification of lysosomes and thus essential for proper lysosomal protein degradation. The impairment in lysosomal function led to a marked reduction in the number of multivesicular bodies (MVBs) targeted for lysosomal degradation, and a corresponding increase in MVBs fusing with the plasma membrane to release their content. Specifically, SIRT1 reduction increased the secretion of exosomes containing unique cargo and the release of soluble hydrolases that typically reside in the lysosome, producing a breast cancer cell secretome that strongly promotes cell invasion and survival. Citation Format: Arash Latifkar, Lu Ling, Xiaoyu Zhang, Claudia Fischbach, Hening Lin, Richard Cerione, Marc Antonyak. Loss of SIRT1 alters the secretome of breast cancer cells by impairing lysosomal integrity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4506.