Phospholipid scramblase 1 as a critical node at the crossroad between autophagy and apoptosis in mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is an aggressive haematological malignancy in which the response to therapy can be limited by aberrantly activated molecular and cellular pathways, among which autophagy was recently listed. Our study shows that the 9-cis-retinoic acid (RA)/Interferon(IFN)-α combination induces protective autophagy in MCL cell lines and primary cultures reducing the extent of drug-induced apoptosis. The treatment significantly up-regulates phospholipid scramblase 1 (PLSCR1), a protein which bi-directionally flips lipids across membranes. In particular, RA/IFN-α combination concomitantly increases PLSCR1 transcription and controls PLSCR1 protein levels via lysosomal degradation. Herein we describe a new function for PLSCR1 as negative regulator of autophagy. Indeed, PLSCR1 overexpression reduced MCL cell susceptibility to autophagy induced by RA/IFN-α, serum deprivation or mTOR pharmacological inhibition. Moreover, PLSCR1 can bind the ATG12/ATG5 complex preventing ATG16L1 recruitment and its full activation, as indicated by co-immunoprecipitation experiments. The combination of doxorubicin or bortezomib with RA/IFN-α strengthened PLSCR1 up-regulation and enhanced apoptosis, as a likely consequence of the blockade of RA/IFN-α-induced autophagy. Immunohistochemical analysis of 32 MCL biopsies revealed heterogeneous expression of PLSCR1 and suggests its possible implication in the response to anticancer therapies, especially to drugs promoting protective autophagy.