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Hsp70, the most highly conserved and abundantly induced of the stress proteins, appears to play dual and opposing roles in cancer. On the one hand, Hsp70 promotes growth and survival of tumor cells by engaging misfolded or aggregated proteins and proteins involved in cell proliferation. As such, it endows tumor cells with stress resistance. However, Hsp70 can also promote tumor immunity by stimulating innate immune mechanisms and enhancing cross-presentation of tumor antigens to lymphocytes. In this chapter, we review these opposing functions of HSP70 in the context of potential strategies for its use as a tool in cancer biology and therapy [ABSTRACT FROM AUTHOR]

Anti-apoptotic functions of heat shock proteins Hsp70 and Hsp27 are well established. However, radiation and genotoxic antineoplastic drugs at clinically relevant doses induce apoptosis mostly in lymphoid cells, while in epithelial tumors they evoke different type of response, mainly senescence and mitotic catastrophe, which leads to loss of clonogenic potential of cells. Here we review old and new data showing that upregulation of Hsp27 or Hsp70 levels protect various tumor cell lines from gamma- and UV-radiation and genotoxic anti-neoplastic drugs. Accordingly, downregulation of Hsp27 or Hsp70 levels by antisense or siRNA sensitizes tumor cells to these agents. Importantly, protection and sensitization by modulation of Hsp27 or Hsp70 levels were manifested not only by modulation of apoptosis, but by clonogenic survival as well, and recent data indicate that these Hsps can suppress also drug-induced senescence. Several studies demonstrated that intrinsic and acquired chemo- and radioresistance in tumor cell lines and in patients with certain forms of cancers can be associated with upregulation of Hsp27 and/or Hsp70. Possible mechanisms of Hsp-induced protection, in particular, modulation of p53-dependent and p53-independent DNA-damaging signaling pathways, are discussed [ABSTRACT FROM AUTHOR]

Many types of cancer cells constitutively express major molecular chaperones at high levels. Recent findings demonstrate that specific depletion of individual chaperones leads to activation of p53 pathway and subsequently triggers cellular senescence. Here we discuss a possibility that in cancer cells high levels of chaperones serve to keep the p53 signaling under control, thus allowing cancer cells to evade the default senescence and form tumors [ABSTRACT FROM AUTHOR]

An estimated 1.15 million new cases of invasive breast cancer occurred in women worldwide in the year 2002 accounting with 410,712 new deaths. The 5-year relative survival rate for localized breast cancer (cancer that has not spread to lymph nodes or other locations outside the breast) has increased from 72% in the 1940s to 97% today. However, the survival rate is lower (79%) in patients with regional spread while for women with distant metastases, the rate is 23% (cancer expected to occur in women in the United States in the year 2004). In this ultimate stage of malignant transformation, the tumors become resistant to most therapies, and the disease is almost incurable. Therefore, therapeutic interventions designed to inhibit metastatic spread of cancer cells are critical. This chapter will briefly cover recent advances in the study of tumor metastasis and the important role played by heat shock protein 25/27 [ABSTRACT FROM AUTHOR]

The small heat shock protein, Hsp27, is elevated in a significant proportion of breast cancers. Over-expression of Hsp27 in breast cancer cells increases anchorage-independent growth, invasiveness and resistance to chemotherapeutic drugs and is associated with poor prognosis and shorter disease free survival in a proportion of cancer patients. Hsp27 acts in a complex manner to elicit diverse effects e.g. increasing survival in response to many stresses by acting either as a molecular chaperone, by association with components of the apoptotic machinery and/or by increasing cellular glutathione to regulate the redox state of the cells. Hsp27 also regulates cytoskeleton organization and stability. Therefore, factors that increase the expression and/or alter the functions of Hsp27 in breast cancer cells can affect disease progression and outcome following treatment. Although Hsp27 expression can be mediated via the classical Heat Shock response following stress, its elevation in breast cancer cells is associated with independent positive regulators which include the estrogen receptor (ER) and transcription factors such as Brn-3b and Sp1. HET/SAF-B negatively regulates Hsp27 in these cells. The effects of Hsp27 are also regulated post-translationally by phosphorylation at specific residues, which alter the oligomerization state of the protein and thus its effects in the cells. The expression, effects and mechanisms by which Hsp27 acts in breast cancer cells are described in this chapter [ABSTRACT FROM AUTHOR]

Human Hsp27 (also denoted HspB1) and αB-crystallin (also denoted HspB5) are major heat-inducible small heat shock proteins (sHsps). These polypeptides share dynamic phosphorylation and oligomeric properties suggesting that different functional forms of these proteins exist. Elevated levels of expression of these sHsps counteract both necrotic and apoptotic cell deaths induced by various stimuli including heat shock, oxidative stress, inflammatory cytokines, death-receptor agonists and apoptotic inducers. In cells exposed to agents or conditions that unfold proteins, such as heat shock, these proteins act as ATP-independent molecular chaperones that can, in concert with other members of the heat shock protein family (i.e. Hsp70, Hsp40 and Hsp90), facilitate the repair or promote the degradation of damaged proteins which are potentially produced in stressed cells. In addition, Hsp27 and αB-crystallin limit the formation of oxidized macromolecules by stimulating the anti-oxidant defences of cell. Hsp27 and αB-crystallin also negatively regulate apoptosis through their ability to interact with several key components of the apoptotic signalling pathway. Moreover, particular oligomeric forms of these polypeptides stabilize the cytoskeleton. The high level of constitutive expression of Hsp27 and αB-crystallin in a wide range of tumors resistant to cancer therapeutics as well as their tumorigenic and metastatic potential designate these proteins as potential targets for future anti-cancer therapeutic strategies [ABSTRACT FROM AUTHOR]

Heat shock factor1, the transcriptional activator of the heat shock protein (hsp) genes is expressed to high level in a number of types of malignancy. HSF1 elevation is coupled to the activation of the c-erb-B2 pathway, a common change associated with breast cancer. HSF1 may exert pro-malignant effects through the activation of hsp gene transcription. The resulting elevated levels of Hsp promote cancer growth through inhibition of apoptosis and promotion of autonomous growth. In addition, HSF1 possesses properties other than those of a transcriptional activator. HSF1 is a gene repressor and binds to the gene co-repressor MTA1 (metastasis associated protein 1). HSF1 may thus function in cancer due to repression of genes that deter malignancy. HSF1 activation may also occur secondarily to treatment with current agents used in chemotherapy such as Hsp90 inhibitors and proteasome inhibitors. Such HSF1 activation may be a confounding effect in chemotherapy. HSF1 thus plays a significant role in tumor growth and response to therapy [ABSTRACT FROM AUTHOR]

Heat shock proteins (Hsp) participate in many events related to cancer as molecular chaperones, starting from the very beginning of carcinogenesis. Several etiological factors involve the Hsp family in their mechanisms of action, including oncogenic viruses, hereditary and non hereditary alterations in tumor suppressors or oncoproteins, hypermethylation, radiation and carcinogenic agents. All of them produce changes in the Hsp response with consequences in cell proliferation, differentiation, inflammation, apoptosis, DNA repair, angiogenesis, metastasis, and drug resistance and in the immunological response mounted by the host. In this chapter we will examine the participation of the Hsp response in tumor cell transformation, either by up-regulation or down-regulation of specific Hsp. This can explain the variations in Hsp expression found in pre-neoplastic and neoplastic human tumors in different tissues and organs. These variations have important clinical consequences in cancer progression, and the exploitation of such knowledge may improve anticancer treatment strategies [ABSTRACT FROM AUTHOR]

The Hsp90 chaperone machine functions as a ‘cradle-to-grave' system for regulating the function, trafficking and turnover of a variety of key ‘client' proteins that are involved in the genesis and progression of cancer, such as p53, RAF, ERBB2, AKT, and CDK4. The multiple effects of Hsp90 on signaling proteins issue from the focal interaction of the multichaperone machinery with protein folding clefts in natively folded proteins. Clefts in the client proteins that are stringently regulated by Hsp90 are inherently ‘metastable' in that they open more readily. These metastable clefts are usually (or always) clefts that must open to bind ligands, such as steroids, heme, or ATP in the protein interior. The Hsp90 chaperone machine acts both to promote cleft opening and to limit further cleft opening by forming stable Hsp90 heterocomplexes with the client protein. By promoting cleft opening, the Hsp90 machinery regulates protein function. By forming stable client protein•Hsp90 heterocomplexes, the machinery performs its protein quality control function in preventing further cleft unfolding that triggers chaperone-dependent ubiquitination and proteasomal degradation. Natural mutations occurring in a variety of proteins associated with human malignancies affect the stability of protein folding clefts to convert them from weak to stringent regulation by Hsp90 and vice versa. Here, we use two well studied Hsp90 client proteins, the glucocorticoid receptor and nNOS, to illustrate how Hsp90 interacts with protein folding clefts to regulate protein activity and turnover [ABSTRACT FROM AUTHOR]