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

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.

Autophagy as a Potential Therapy for Malignant Glioma

“…In cancer, a mutated p 53 decreases autophagy and favors the proliferation of tumoral cells, and thus it could be a therapeutic target. In autophagy, anti-apoptotic proteins, such as Bcl-xL and XIAP are also degraded, thus promoting the removal of tumor cells by cytotoxic lymphocytes and NK cells through the Granzyme pathway [ 86 ]. In fact, p53 activates autophagy; conversely, autophagy suppresses the expression of p53, thus promoting cancer proliferation [ 87 ].…”

Autophagy, the innate immune response and cancer

“…Breast cancer cells in hypoxic conditions were able to evade NK cell killing via the activation of autophagy and the subsequent degradation of granzyme B in vitro [102]. However, in non-hypoxic conditions restoration of p53 function in breast cancer cells increased their susceptibility to NK cell cytotoxicity via autophagic sequestering of antiapoptotic Bcl-2 family members, which potentiated granzyme B-induced apoptosis [103]. It is important to determine the effect of autophagy on tumour cell susceptibility to NK cell cytotoxicity in vivo as differences in the TME could alter the ability of autophagy to inhibit/enhance NK cell-induced apoptosis in tumour cells.…”

The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe?

“…With the expression of nuclear p53 stimulated by starvation conditions, the activated AMPK induces autophagy through the TSC1/TSC2 complex and mTOR pathway ( Figure 4 ) ( Hu et al, 2019 ; Gao et al, 2020 ). Chollat-Namy et al (2019) have found that p53 upregulates the expression of its downstream targets Sestrin-1 and Sestrin-2, which further activate AMPK through phosphorylating AMPK at Thr172, subsequently leading to the dephosphorylation of mTORC1 at S2448 and the induction of autophagy. Damage-regulated autophagy modulator (DRAM) and death-associated protein kinase 1 (DAPK1) are other important downstream targets of p53 and have been reported to induce autophagy ( Crighton et al, 2006 ; Zhou et al, 2016 ; Hu et al, 2019 ).…”