Abstract
The main tumor suppressor function of p53 as a “guardian of the genome” is to respond to cellular stress by transcriptional activation of apoptosis, growth arrest, or senescence in damaged cells. Not surprisingly, mutations in the p53 gene are the most frequent genetic alteration in human cancers. Importantly, mutant p53 (mutp53) proteins not only lose their wild-type tumor suppressor activity but also can actively promote tumor development. Two main mechanisms accounting for mutp53 proto-oncogenic activity are inhibition of the wild-type p53 in a dominant-negative fashion and gain of additional oncogenic activities known as gain-of-function (GOF). Here, we discuss a novel mechanism of mutp53 GOF, which relies on its oncogenic cooperation with the heat shock machinery. This coordinated adaptive mechanism renders cancer cells more resistant to proteotoxic stress and provides both, a strong survival advantage to cancer cells and a promising means for therapeutic intervention.
Highlights
Pancreatic and non-small-cell lung cancer [both of which have high prevalence of mutp53 [1] and are commonly treated with epidermal growth factor receptor (EGFR) inhibitor Erlotinib], and possibly esophageal cancer [43% mutp53-positive [1], 23% Her2-positive]
Mutp53 levels were not examined in this study [31], it is tempting to speculate that they were reduced in heat shock factor 1 (HSF1)-deficient tumors as a result of insufficient transcriptional upregulation of HSP90, leading to restrained malignant transformation. In support of this idea, we previously showed that shRNA-mediated knockdown of HSF1 in mutp53 cancer cells induces rapid destabilization of mutp53 and reduces its half-life, along with reduction of HSP90 levels [29]
We propose that mutp53 through enhanced recycling [12] and/or stability of EGFR and Her2/ErbB2 – augments MAPK and phosphoinositide-3 kinase (PI3K) signaling, leading to phospho-activation of HSF1
Summary
Pancreatic and non-small-cell lung cancer [both of which have high prevalence of mutp53 [1] and are commonly treated with EGFR inhibitor Erlotinib], and possibly esophageal cancer [43% mutp53-positive [1], 23% Her2-positive]. (2015) Mutant p53 – heat shock response oncogenic cooperation: a new mechanism of cancer cell survival. It augments the prosurvival heat shock response machinery via activating the master transcriptional regulator heat shock factor 1 (HSF1), which in a positive feed-forward loop further stabilizes mutp53 itself, along with other tumor-promoting clients [13].
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