Abstract
Missense mutations in the TP53 gene produce mutant p53 (mutp53) proteins which may acquire oncogenic properties favoring chemoresistance, cell migration, and metastasis. The exploitation of cellular pathways that promote mutp53 degradation may reduce cell proliferation and invasion as well as increase the sensitivity to anticancer drugs, with a strong impact on current cancer therapies. In the last years, several molecules have been characterized for their ability to induce the degradation of mutp53 through the activation of autophagy. Here, we investigated the correlation between autophagy and mutp53 degradation induced by suberoylanilide hydroxamic acid (SAHA), an FDA-approved histone deacetylase inhibitor. In the human cancer lines MDA-MB-231 (mutp53-R280K) and DLD1 (mutp53-S241F), SAHA induced a significant mutp53 degradation. However, such degradation correlated with autophagy induction only in MDA-MB-231 cells, being counteracted by autophagy inhibition, which also increased SAHA-induced cell death. Conversely, in DLD1 cells SAHA triggered a low level of autophagy despite promoting a strong decrease in mutp53 level, and autophagy inhibition did not change either mutp53 levels or sensitivity to this drug. We conclude that autophagy can be a relevant pathway for mutp53 degradation induced by SAHA, but its contribution to mutp53 destabilization and the consequences on cell death are likely context-dependent.
Highlights
The p53 tumor suppressor protein has a central role in cell homeostasis due to its involvement in many pathways that regulate cell cycle arrest and proliferation, cell response to stress, DNA repair, cell death and autophagy [1]
The mutp53 degradation was evaluated by immunostaining with an anti-p53 antibody (Figure 2A, upper panels); the green nuclear staining diminished after suberoylanilide hydroxamic acid (SAHA) exposure of MDA-MB-231 cells, indicating a lower amount of p53 protein in the nuclei
In order to correlate the SAHA-induced mutp53 degradation in MDA-MB-231 cells with its autophagic potential, the endogenous Microtubule-associated protein Light Chain 3 (LC3) protein was analyzed by immunofluorescence assays with an antibody against endogenous LC3 protein (Figure 2A)
Summary
The p53 tumor suppressor protein has a central role in cell homeostasis due to its involvement in many pathways that regulate cell cycle arrest and proliferation, cell response to stress, DNA repair, cell death and autophagy [1]. TP53 is the most frequently mutated gene in human cancers and the presence of mutant p53 proteins (mutp53s) in tumors often correlates with a bad prognosis [2]. Not exhibited by the wild-type (wt) protein, promote malignancy and resistance to chemotherapy. These features, called gain of functions, were first demonstrated after the introduction of mutp in TP53 null cancer cells [3]. Other studies have thoroughly demonstrated that the elimination of mutp decreases the proliferation of tumor cells, inhibits invasion and metastasis, and sensitizes tumor cells to genotoxic agents that are used in chemotherapy [8,9]. Inducing mutp degradation would represent a useful therapeutic approach
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