The pharmalogical reactivation of p53 function improves breast tumor cell lysis by granzyme B and NK cells through induction of autophagy

Chollat-Namy, Ben Safta-Saadoun, Haferssas, Meurice, Chouaib, Thiery (2019) The pharmalogical reactivation of p53 function improves breast tumor cell lysis by granzyme B and NK cells through induction of autophagy Cell Death Dis (IF: 9) 10(10) 695

Abstract

Cytotoxic T lymphocytes (CTL) and natural killer cells (NK)-mediated elimination of tumor cells is mostly dependent on Granzyme B apoptotic pathway, which is regulated by the wild type (wt) p53 protein. Because TP53 inactivating mutations, frequently found in human tumors, could interfere with Granzyme B-mediated cell death, the use of small molecules developed to reactivate wtp53 function in p53-mutated tumor cells could optimize their lysis by CTL or NK cells. Here, we show that the pharmalogical reactivation of a wt-like p53 function in p53-mutated breast cancer cells using the small molecule CP-31398 increases their sensitivity to NK-mediated lysis. This potentiation is dependent on p53-mediated induction of autophagy via the sestrin-AMPK-mTOR pathway and the ULK axis. This CP31398-induced autophagy sequestrates in autophagosomes several anti-apoptotic proteins, including Bcl-XL and XIAP, facilitating Granzyme B-mediated mitochondrial outer membrane permeabilization, caspase-3 activation and Granzyme B- or NK cell-induced apoptosis. Together, our results define a new way to increase cytotoxic lymphocyte-mediated lysis of p53-mutated breast cancer cell, through a p53-dependent autophagy induction, with potential applications in combined immunotherapeutic approaches.

Links

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754511
http://www.ncbi.nlm.nih.gov/pubmed/31541080
http://dx.doi.org/10.1038/s41419-019-1950-1

Similar articles

Tools

Export to RIS