Implication of Heat Shock Factors in Tumorigenesis: Therapeutical Potential

Abstract

Heat Shock Factors (HSF) form a family of transcription factors (four in mammals) which were named according to the discovery of their activation by a heat shock. HSFs trigger the expression of genes encoding Heat Shock Proteins (HSPs) that function as molecular chaperones, contributing to establish a cytoprotective state to various proteotoxic stresses and in pathological conditions. Increasing evidence indicates that this ancient transcriptional protective program acts genome-widely and performs unexpected functions in the absence of experimentally defined stress. Indeed, HSFs are able to re-shape cellular pathways controlling longevity, growth, metabolism and development. The most well studied HSF, HSF1, has been found at elevated levels in tumors with high metastatic potential and is associated with poor prognosis. This is partly explained by the above-mentioned cytoprotective (HSP-dependent) function that may enable cancer cells to adapt to the initial oncogenic stress and to support malignant transformation. Nevertheless, HSF1 operates as major multifaceted enhancers of tumorigenesis through, not only the induction of classical heat shock genes, but also of “non-classical” targets. Indeed, in cancer cells, HSF1 regulates genes involved in core cellular functions including proliferation, survival, migration, protein synthesis, signal transduction, and glucose metabolism, making HSF1 a very attractive target in cancer therapy. In this review, we describe the different physiological roles of HSFs as well as the recent discoveries in term of non-cogenic potential of these HSFs, more specifically associated to the activation of “non-classical” HSF target genes. We also present an update on the compounds with potent HSF1-modulating activity of potential interest as anti-cancer therapeutic agents.

Environmental stress induces trinucleotide repeat mutagenesis in human cells

“…Cancer cells often further their survival and growth in hostile environments by increasing the expression of key SRFs such as CIRP, HSF1, HIF1, and NRF2 (45)(46)(47)(48). One of the consequences of SRF expression in hypoxic cancer cells is increased mutagenesis (29), similar to the SIM of TNRs observed here.…”

Tyrosine kinase inhibitor tyrphostin AG490 triggers both apoptosis and autophagy by reducing HSF1 and Mcl-1 in PEL cells

“…HSF1 inhibition, shown to be effective in reducing cell survival of several cancer cell types [15], has not been yet investigated in PEL cells. To evaluate the effect mediated by its reduction, we knocked down this molecule by specific siRNA and observed that it led to reduction of PEL cell survival (Fig.…”

“…In particular, phospho-STAT3 interacts with HSF1 promoting its transcriptional activity [13]. Besides inducing the expression of HSPs, HSF1 positively regulates other prosurvival pathways in cancer cells, that is the reason why it is itself emerging as a promising target in anticancer therapy [14,15]. However, its constitutive expression and its role in PEL cell survival have not been investigated yet.…”

Sugar-decorated mesoporous silica nanoparticles as delivery vehicles for the poorly soluble drug celastrol enables targeted induction of apoptosis in cancer cells

“…[8] which has the ability to induce cell death through destabilizing the mitotic spindle and by disrupting topoisomerase II function, thereby leading to DNA fragmentation [9][10][11][12]. Because cancer cells have an increased mitotic rate, they are consequently susceptible to the action of celastrol [13,14]. As well as its apoptosis-inducing effects, celastrol has at lower concentrations the ability to activate the heat shock response that leads to cytoprotection of the cell [15].…”