Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update

Ciocca, Daniel R.; Arrigo, André Patrick; Calderwood, Stuart K.

doi:10.1007/s00204-012-0918-z

Cited by 232 publications

(273 citation statements)

References 357 publications

(387 reference statements)

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“…It thus is notable that PGC-1α also can regulate these aspects of HSF1 activity. Specifically, cancer cells are considered to be highly dependent on HSF1 activity, which regulates several transcriptional programs that include those controlling cell cycle, DNA damage repair, and protein translation (17,19). Our analysis shows that at least some of these programs are regulated directly by PGC-1α; future studies will explore the possibility that additional non-HSR transcriptional programs are directly regulated by the action of PGC-1α on HSF1.…”

Section: Discussionmentioning

confidence: 81%

“…Although HSF1 has long been known to bind to and activate promoters of various HSP genes as part of the HSR, it has been described more recently as a regulator of many additional transcriptional programs that include those controlling cell survival, ion transport, signal transduction, and other cellular processes (12,14,15). Consistent with its versatile functions in the regulation of numerous transcriptional programs, HSF1 also has been implicated in certain pathological conditions that include neurodegeneration and cancer (16,17). Although HSF1 may not be strictly required for normal cellular or organismal survival in mammals (18), the role of HSF1 in regulating non-HSR targets, including those related to DNA damage repair and the cell cycle, recently has emerged as critical for cancer cell survival (19)(20)(21).…”

mentioning

confidence: 99%

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Direct link between metabolic regulation and the heat-shock response through the transcriptional regulator PGC-1α

Minsky

Roeder

2015

Proc. Natl. Acad. Sci. U.S.A.

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In recent years an extensive effort has been made to elucidate the molecular pathways involved in metabolic signaling in health and disease. Here we show, surprisingly, that metabolic regulation and the heat-shock/stress response are directly linked. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a critical transcriptional coactivator of metabolic genes, acts as a direct transcriptional repressor of heat-shock factor 1 (HSF1), a key regulator of the heat-shock/stress response. Our findings reveal that heatshock protein (HSP) gene expression is suppressed during fasting in mouse liver and in primary hepatocytes dependent on PGC-1α. HSF1 and PGC-1α associate physically and are colocalized on several HSP promoters. These observations are extended to several cancer cell lines in which PGC-1α is shown to repress the ability of HSF1 to activate gene-expression programs necessary for cancer survival. Our study reveals a surprising direct link between two major cellular transcriptional networks, highlighting a previously unrecognized facet of the activity of the central metabolic regulator PGC-1α beyond its well-established ability to boost metabolic genes via its interactions with nuclear hormone receptors and nuclear respiratory factors. Our data point to PGC-1α as a critical repressor of HSF1-mediated transcriptional programs, a finding with possible implications both for our understanding of the full scope of metabolically regulated target genes in vivo and, conceivably, for therapeutics. metabolism | transcription | stress response

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Section: Discussionmentioning

confidence: 81%

mentioning

confidence: 99%

Direct link between metabolic regulation and the heat-shock response through the transcriptional regulator PGC-1α

Minsky

Roeder

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The expression of HSPs is mainly regulated by HSF1 (17,18). HSPs (12,56,57) as well as HSF1 (19-26) are abundantly expressed in human cancer cells of various origins, and HSPs (12,56,57) and HSF1 (12,(25)(26)(27)(28)(29) play critical roles in the initiation, proliferation and maintenance of cancer. Thus, the combination of HT and HSF1-targeting may be an attractive option and worthy of further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, cancer cells are generally exposed to more stresses compared with normal cells (55). Several types of tumors contain high expression levels of one or more HSPs (Hsp27, Hsp40, Hsp60, Hsp70, Hsp90 and/or Hsp110) compared with adjacent normal tissues (12,56,57). A significant elevation of HSF1 has been reported in a wide variety of cancer cells or tumor tissues in nonclinical studies (19-26) (Table I).…”

Section: Hsf1 and Cancermentioning

confidence: 99%

Targeting heat shock transcription factor 1 for novel hyperthermia therapy

Tabuchi

Kondo

2013

International Journal of Molecular Medicine

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Abstract. Hyperthermia (HT) has shown promising antitumor effects against various types of malignant tumors, and its pleiotropic effects support its combined use with radiotherapy and/or chemotherapy. However, HT is rendered less effective by the acquisition of thermoresistance in tumors, which arises through the elevation of heat shock proteins (HSPs) or other tumor responses. In mammals, the induction of HSPs is principally regulated at the transcriptional level by the activation of heat shock transcription factor 1 (HSF1). This transactivator has been shown to be abundantly expressed in a wide variety of tumors in humans. In addition, HSF1 participates in the initiation, proliferation and maintenance of tumors. Of note, HSF1 silencing has been shown to prevent the progression of tumors and to enhance their sensitivity to HT. Here, we review the physiological and pathological roles of HSF1 in cancer cells, and discuss its potential as a therapeutic target for HT therapy. Contents1. Introduction 2. Function of HSF1 3. HSF1 and cancer 4. HSF1 and hyperthermia 5. Discussion IntroductionHyperthermia (HT) is considered to have potential as a cancer treatment modality (1). HT in combination with radiotherapy and/or chemotherapy has been used for various types of cancer, and the anticancer effects of such combinations have been verified in many clinical trials (1-7). One of the problems with HT therapy is the acquisition of thermoresistance against heat stress (8-12). In general, cells have protective functions for various stressors that occur from outside of the cell. Heat shock proteins (HSPs), molecular chaperones with strong cytoprotective and antiapoptotic properties, are induced by a wide variety of stresses, particularly heat stress (13-16); they are also induced by treatment with HT, and, thus, it has been considered that HSPs play a role in the acquisition of thermoresistance in cells (10-12). In mammals, the expression of HSPs is mainly regulated by heat shock transcription factor 1 (HSF1) (17,18). Elevation of HSF1 has been observed in several types of human tumor tissues (19-26), and it has been shown to participate in the initiation, proliferation and maintenance of tumors (12,(25)(26)(27)(28)(29). Notably, both inhibition of the expression of HSF1 and the functional loss of HSF1 have been suggested to enhance the sensitivity to HT under basic experimental conditions (29)(30)(31)(32)(33)(34)(35)(36)(37)(38). In the present review, the physiological and pathological roles of HSF1 in cancer cells are summarized, and the potential of HSF1 as a therapeutic target for HT therapy is discussed. Function of HSF1The heat-shock response, which is a universal cellular response to heat, is a critical cellular event for cell adaptation. Heat stress elicits a wide spectrum of stress responses, including an induction of HSPs, protein aggregation, an imbalance of protein homeostasis, DNA and RNA damage, reactive oxygen species production, cell growth arrest and cell death in mammalian cells. HSPs are characterized as mo...

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“…While Hsp70 and its co-chaperones are believed to act in concerted fashion we have shown the individual members can have differing effects on the substrate molecule [27]. Hsp70 cycle thus aimed to maintain homeostasis and the quality of protein inadvertently or under duress helps healthy folding of oncogenic proteome facilitating tumor genesis [28].…”

Section: Hsp70mentioning

confidence: 96%