Loss of Sirtuin 1 Alters the Secretome of Breast Cancer Cells by Impairing Lysosomal Integrity

Abstract

Highlights d SIRT1 expression is frequently decreased in aggressive breast cancers d Reducing SIRT1 levels in breast cancer cells impairs lysosomal acidification d Loss of SIRT1 gives rise to a secretome that promotes cell invasion and survival d SIRT1 mediates these effects by regulating V-ATPase expression

Senescent stromal cells promote cancer resistance through SIRT1 loss-potentiated overproduction of small extracellular vesicles

“…3I). Thus, our data consistently demonstrated that SIRT1 loss causes lysosomal de-acidification and is responsible for sEV overproduction via ATP6V1A downregulation in SEN cells, a mechanism reported for certain cancer cell types 35 .…”

“…Simultaneously, SIRT1 loss is responsible for ATP6V1A downregulation, resulting in defective lysosomal acidification and sEV overproduction by senescent cells. The data are reminiscent of a recent study which demonstrated that genetic or pharmacological inhibition of SIRT1 destabilizes the mRNA of the lysosomal V-ATPase proton pump and causes its downregulation (ATP6V1A), leading to deficient lysosomal acidification, MVB enlargement and enhanced exosomes production 35 . While our observation was mainly regarding senescent stromal cells, distinct from the discovery recently made in human breast cancer cells, a similarly occurring MVB expansion revealed by our in vitro assays suggests that senescent stromal cells somehow resemble cancer cells with regard to sEV biogenesis.…”

“…There is a growing interest in the discovery of small molecules modifying sirtuin activities, although most sirtuin activators have been described intensively for SIRT1 58 . Specifically, SIRT1 has been suggested to play multiple and, in some cases, contradictory roles in cancer, as that SIRT1 can function as either a tumor suppressor or tumor promoter, depending on the tissue type and pathological context 35 . In vivo stimulation of SIRT1 either with agonist or NAD + precursors can extend the lifespan of mice and protect against diverse aging-related diseases 59 .…”

“…It was suggested that dysfunctional lysosome or autophagy can promote EV biogenesis through modifying the fate of MVBs, the direct cytoplasmic source of exosomes 33,34 . A recent study further revealed that reduced SIRT1 expression in breast cancer cells can modify lysosomal activity, resulting in enhanced release of exosomes from these cells and significant changes in their exosome composition 35 .…”

Extracellular vesicles and their roles in stem cell biology

“…Recently, it was discovered that the NAD + ‐dependent lysine deacetylase sirtuin 1 (Sirt1) is an important regulator of exosome biogenesis in breast cancer cells. Downregulation of Sirt1 expression impaired lysosomal pH and activity, and as a consequence, resulted in more MVBs fusing with the plasma membrane and releasing exosomes, as opposed to fusing with lysosomes where their exosomal contents are degraded …”