Selective suppression of lymphomas by functional loss of Hsf1 in a p53-deficient mouse model for spontaneous tumors

Jn, Min; Huang, Lei; Db, Zimonjic; Moskophidis, Demetrius; Nf, Mivechi

doi:10.1038/sj.onc.1210317

Cited by 146 publications

(151 citation statements)

References 30 publications

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“…In line with these results, different animal experiments with genetically modified mice showed an essential role of HSF1 in tumor development (26,27,63) (Table II).…”

Section: Hsf1 and Cancersupporting

confidence: 69%

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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“…In line with these results, different animal experiments with genetically modified mice showed an essential role of HSF1 in tumor development (26,27,63) (Table II).…”

Section: Hsf1 and Cancersupporting

confidence: 69%

Targeting heat shock transcription factor 1 for novel hyperthermia therapy

Tabuchi

Kondo

2013

International Journal of Molecular Medicine

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“…Although still not well understood, the functions of HSF1 are beyond the classical induction of heat shock responses. Recent reports have shown that HSF1 may have an important role in cancer development (Khaleque et al, 2005(Khaleque et al, , 2008Min et al, 2007). A recent study showed that the elimination of HSF1 protects mice from tumors induced by mutations of the Ras oncogene or a hot spot mutation in the tumor suppressor p53 (Dai et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth

et al. 2009

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ErbB2 has been shown to activate signaling molecules that may regulate glucose metabolism. However, there is no evidence reported to directly link ErbB2 to glycolysis, and the mechanism underlying ErbB2-enhanced glycolysis is poorly understood. In this study, we investigated the role and mechanism of ErbB2 in regulating glycolysis. We found that ErbB2-overexpressing cells possessed a significantly higher level of glycolysis when compared to the ErbB2-low-expressing cells, and the downregulation of ErbB2 markedly decreased glycolysis. Overexpression of ErbB2 increased the expression of glycolysis-regulating molecules lactate dehydrogenase A (LDH-A) and heat shock factor 1 (HSF1). ErbB2 activated HSF1, indicated by the increased HSF1 trimer formation, and promoted HSF1 protein synthesis. HSF1 bound to LDH-A promoter and the downregulation of HSF1 reduced the expression of LDH-A and subsequently decreased cancer cell glycolysis and growth. Moreover, the glycolysis inhibitors, 2-deoxyglucose and oxamate, selectively inhibited the growth of ErbB2-overexpressing cells. Taken together, this study shows that in human breast cancer cells, ErbB2 promotes glycolysis at least partially through the HSF1-mediated upregulation of LDH-A. This pathway may have a major role in regulating glucose metabolism in breast cancer cells. These novel findings have important implications for the design of new approaches to target ErbB2-overexpressing breast cancers.

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“…The roles of HSPs in tumor development may also be related to their functions in the development of tolerance to applied stress (Li and Werb, 1982). However, the precise relationships between HSFs and HSPs during cancer development have not been clearly defined and relatively few papers about the role of HSF1 in cancer or carcinogenesis are available (Cen et al, 2004;Wang et al, 2004;Min et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

A novel function for HSF1-induced mitotic exit failure and genomic instability through direct interaction between HSF1 and Cdc20

Lee

et al. 2007

Oncogene

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Although heat-shock factor (HSF) 1 is a known transcriptional factor of heat-shock proteins, other pathways like production of aneuploidy and increased protein stability of cyclin B1 have been proposed. In the present study, the regulatory domain of HSF1 (amino-acid sequence 212-380) was found to interact directly with the amino-acid sequence 106-171 of Cdc20. The association between HSF1 and Cdc20 inhibited the interaction between Cdc27 and Cdc20, the phosphorylation of Cdc27 and the ubiquitination activity of anaphase-promoting complex (APC). The overexpression of HSF1 inhibited mitotic exit and the degradations of cyclin B1 and securin, which resulted in production of aneuploidy and multinucleated cells, but regulatory domain-deficient HSF1 did not. Moreover, HSF1-overexpressing cells showed elevated levels of micronuclei and genomic alteration. The depletion of HSF1 from cells highly expressing HSF1 reduced nocodazole-mediated aneuploidy in cells. These findings suggest a novel function of HSF1 frequently overexpressed in cancer cells, to inhibit APC/C activity by interacting with Cdc20, and to result in aneuploidy development and genomic instability.

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Selective suppression of lymphomas by functional loss of Hsf1 in a p53-deficient mouse model for spontaneous tumors

Cited by 146 publications

References 30 publications

Targeting heat shock transcription factor 1 for novel hyperthermia therapy

Targeting heat shock transcription factor 1 for novel hyperthermia therapy

Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth

A novel function for HSF1-induced mitotic exit failure and genomic instability through direct interaction between HSF1 and Cdc20

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