Critical role of CAV1/caveolin-1 in cell stress responses in human breast cancer cells via modulation of lysosomal function and autophagy

Abstract

CAV1 (caveolin 1, caveolae protein, 22kDa) is well known as a principal scaffolding protein of caveolae, a specialized plasma membrane structure. Relatively, the caveolae-independent function of CAV1 is less studied. Autophagy is a process known to involve various membrane structures, including autophagosomes, lysosomes, and autolysosomes for degradation of intracellular proteins and organelles. Currently, the function of CAV1 in autophagy remains largely elusive. In this study, we demonstrate for the first time that CAV1 deficiency promotes both basal and inducible autophagy. Interestingly, the promoting effect was found mainly in the late stage of autophagy via enhancing lysosomal function and autophagosome-lysosome fusion. Notably, the regulatory function of CAV1 in lysosome and autophagy was found to be caveolae-independent, and acts through lipid rafts. Furthermore, the elevated autophagy level induced by CAV1 deficiency serves as a cell survival mechanism under starvation. Importantly, downregulation of CAV1 and enhanced autophagy level were observed in human breast cancer cells and tissues. Taken together, our data reveal a novel function of CAV1 and lipid rafts in breast cancer development via modulation of lysosomal function and autophagy.

Overexpression of caveolin-1 reduces Taxol resistance in human osteosarcoma cells by attenuating PI3K-Akt-JNK dependent autophagy

“…CAV-1 inhibition has previously been shown to be correlated with autophagic induction in human breast cancer cells (13). Autophagy is a regulatory mechanism that protects cells from stress; however, prolonged consistent autophagy may cause type II programmed cell death (4).…”

“…A recent study indicated that caveolin-1 (CAV-1) was highly expressed in cancer stem cells and decreased cells' chemosensitivity (12). CAV-1 inhibition has previously been shown to be associated with autophagic induction in human breast cancer cells (13). Furthermore, it has been demonstrated that CAV-1 deletion increases basal autophagy, due to an increase in the complex of autophagy-related proteins 5 and 12 (Atg5-Atg12), and that a CAV-1 binding motif mutation broke this complex and accelerated autophagy (14).…”

Regulation of Phagolysosomal Digestion by Caveolin-1 of the Retinal Pigment Epithelium Is Essential for Vision

“…Fibroblasts and breast cancer cells in culture lacking caveolin-1 increase autophagy markers and LysoTracker-positive compartments in a response to increased oxidative stress (51,52). Notably, non-canonical autophagy shares components with clearance phagocytosis pathways (53,54).…”

Role of autophagy in the regulation of epithelial cell junctions

“…76 Cav-1 deficiency also promotes both basal and inducible autophagy, particularly by increasing lysosomal function and autophagosomelysosome fusion as a cell survival mechanism under starvation. 77 TJ protein occludin, [78][79][80] AJ protein b-catenin, 81,82 and GJ protein connexins 83 are known to be associated with caveolins. Macropinocytosis is another mode of vesicular trafficking of junctional proteins 84 that is regulated by autophagy.…”