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

Abstract

Heat shock proteins (HSP) are a subset of the molecular chaperones, best known for their rapid and abundant induction by stress. HSP genes are activated at the transcriptional level by heat shock transcription factor 1 (HSF1). During the progression of many types of cancer, this heat shock transcriptional regulon becomes co-opted by mechanisms that are currently unclear, although evidently triggered in the emerging tumor cell. Concerted activation of HSF1 and the accumulation of HSPs then participate in many of the traits that permit the malignant phenotype. Thus, cancers of many histologies exhibit activated HSF1 and increased HSP levels that may help to deter tumor suppression and evade therapy in the clinic. We review here the extensive work that has been carried out and is still in progress aimed at (1) understanding the oncogenic mechanisms by which HSP genes are switched on, (2) determining the roles of HSF1/HSP in malignant transformation and (3) discovering approaches to therapy based on disrupting the influence of the HSF1-controlled transcriptome in cancer.

Fig.1

The HSF1 / HSP transcriptome regulates multiple traits associated with malignant transformation and tumorigenesis.

Fig. 2

A circuit diagram of the programmed cell death pathways observed in cancer indicating the involvement of HSPs at multiple stages.

Fig. 3

Role of HSF1 and HSPs in cancer cell biology. Activation of HSF1 and elevated expression of HSPs may mediate multiple stages in malignant cell development, including normal cell transformation, stemness, EMT, angiogenesis and metastasis. (NC: normal cell; CSC: cancer stem cell; EMT: epithelial mesenchymal transition)

Fig. 4

Potential roles for HSF1 and HSPs in drug resistance of cancer cells. (Left side) HSF1 appears to regulate multiple pathways involved in expression of the multiple drug resistance phenotype (MDR) that leads to escape from chemotherapy mediated cell killing. (Right side) HSPs, most notably HSP27 and Hsp70 can suppress the activity of p53 and reduce apoptosis and senescence associated with transformation as well as therapy.

Fig. 5

Potential role for HSPs in the resistance to radiation therapy, through: (1) mediation of p53 expression, (2) fostering of angiogenesis and oxygen supply, (3) elevation in glutathione and reduction in oxidative stress and (4) fostering of telomerase and reduction in chromosome damage.