Heat shock proteins in cancer: chaperones of tumorigenesis

Calderwood, Stuart K.; Khaleque, Abdul; Sawyer, Douglas B.; Ciocca, Daniel R.

doi:10.1016/j.tibs.2006.01.006

Cited by 861 publications

(740 citation statements)

References 86 publications

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“…Five types of primary HSPs are currently known, and they are designated according to their molecular weight (HSP27, 60, 70, 90 and 110). 17 HSPs bind and stabilize proteins to prevent the creation of aggregates during protein synthesis, transmembrane transport or stress, such as high temperatures. 18 There are some cochaperones of low molecular weight that often form a biologically active complex.…”

Section: Discussionmentioning

confidence: 99%

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Immunohistochemical analysis of possible chemoresistance markers identified by micro-arrays on serous ovarian carcinomas

et al. 2008

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Using the DNA microarray technology, we have identified genes that are differentially expressed in chemosensitive and chemoresistant ovarian serous papillary carcinomas and could potentially distinguish ovarian cancer patients based on their response to chemotherapy. The present study aims to evaluate the clinical usefulness of overexpression of selected genes by immunohistochemistry. Our cohort included 158 women who were operated on and received chemotherapy for an advanced serous papillary ovarian carcinoma (FIGO stages III and IV). The end point used in this study was progression-free survival. Immunohistochemistry was performed on microarray blocks containing all 158 cases. Twelve commercially available antibodies were selected. Of them, 10 corresponded to differentially expressed genes in our micro-array study and p53 and Ki67 were included. Antibodies were obtained for the following selected genes: GSTA1, MMP1, FOSB, CTSL2, HSP10, CD36, CXCL2, RBBP7, Siva, and PTGDS. Cox proportional hazards models, adjusted for standard risk factors, were used to estimate the associations between the markers and progression-free survival. No association was found between mRNA level and protein expression by immunohistochemistry. In multivariate analyses, patients whose tumors overexpressed HSP10 had a lower risk of progression than those with low expression (HR: 0.6; CI: 0.42-0.87; P ¼ 0.007). High level of proliferation (Ki67) tended to be associated with a lower risk of progression (HR: 0.72; CI: 0.51-1.03; P ¼ 0.07) whereas MMP1 overexpression tended to be associated with a higher risk of progression (HR: 1.61; CI: 0.94-2.79; P ¼ 0.08). Our study shows that gene expression analysis coupled with immunohistochemistry allowed the identification of HSP10 as an independent factor of progression-free survival. Modern Pathology (2008Pathology ( ) 21, 1002Pathology ( -1010 doi:10.1038/modpathol.2008 published online 23 May 2008 Keywords: serous ovarian carcinoma; chemoresistance; HSP10; DNA microarray; immunohistochemistry Ovarian cancer is responsible for more cancer deaths among women in the Western world than any other gynecologic malignancy. 1 An initial surgical approach is essential for aggressive cytoreduction and proper staging of the disease, since minimal residual tumor after surgery is a major factor of better response to chemotherapy and survival. 2 Intravenous combinated chemotherapy with taxol plus carboplatin is the current regimen of choice for the treatment of advanced ovarian cancer and is followed by a 50% complete pathologic remission rate. 3 Resistance to chemotherapy is, however, a major concern. Indeed, although significant proportions of women respond to chemotherapy, the majority of responders (approximately 60-75%) eventually relapses and dies from recurrent disease while 20-30% of patients never experience a clinical remission. 4 Chemotherapy resistance in ovarian

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Section: Discussionmentioning

confidence: 99%

“…The HSP10-HSP40 complex is known to facilitate interactions between primary HSP and the substrate. 17 The HSP10-HSP60 complex is involved in apoptosis through caspase activation. 19 Therefore, in cases with constitutively low HSP10 levels, chemoresistance, as we observed, may be explained by a lack of capacity to induce apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical analysis of possible chemoresistance markers identified by micro-arrays on serous ovarian carcinomas

et al. 2008

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“…Overexpression of HSPs has been observed in several cancer cells and members in this family of proteins have been suspected as one of the causative agents for resistance of cancer cells against radiation treatment and chemotherapeutic agents [61,62]. They found that zerumbone was inserted between disulfide linkages in the HSP27 dimers and this cross-linking altered the normal dimerization of the protein.…”

Section: Cem-ss Cells (T-acute Lymphoblastic Leukemia)mentioning

confidence: 99%

Key cell signaling pathways modulated by zerumbone: Role in the prevention and treatment of cancer

Prasannan

Kalesh

Shanmugam

et al. 2012

Biochemical Pharmacology

128

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“…Hsp90 is absolutely essential for the stabilization/ maturation of nuclear hormone receptors, transcription factors, and protein kinases that are commonly misregulated during tumorigenesis [8]. It also serves to buffer the effects of transformation by preventing the aggregation of aberrantly expressed proteins, whose accumulation would otherwise result in toxic stress signals and progression to programmed cell death [53]. As many of the client proteins of Hsp90 are linked to growth signal pathways, Hsp90 is viewed as key player in the subversion of normal cells toward unrestrained proliferation.…”

Section: Chaperoning Tumorigenesismentioning

confidence: 99%

Hsp90—From signal transduction to cell transformation

Brown

Zhu

Schmidt

et al. 2007

Biochemical and Biophysical Research Communications

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The molecular chaperone, Hsp90, facilitates the maturation and/or activation of over 100 'client proteins' involved in signal transduction and transcriptional regulation. Largely an enigma among the families of heat shock proteins, Hsp90 is central to processes broadly ranging from cell cycle regulation to cellular transformation. Here we review the contemporary body of knowledge regarding the biochemical mechanisms of Hsp90 and update the most current paradigms defining its involvement in both normal and pathological cell physiology. KeywordsHsp90; heat shock protein; molecular chaperone; ATPase; genetic capacitor Hsp90 defines a family of molecular chaperones that are highly conserved from prokaryotes to eukaryotes [1][2][3][4][5]. Nonessential for normal growth in most bacteria, Hsp90 is abundantly expressed in higher eukaryotes where it has been shown to be necessary for viability [6,7]. It functions as a homodimer that associates with co-chaperones to catalyze the maturation and/ or activation of over 100 substrate proteins that are known to be involved in cell regulatory pathways [5]. These 'client proteins' include protein kinases, nuclear hormone receptors, transcription factors, and an array of other essential proteins [8]. While much is known regarding the ATPase-driven conformational cycling of Hsp90, the precise physical effects imparted by this chaperone that serve to activate its substrates are still poorly understood [5]. Hsp90 architectureThree highly conserved domains comprise the structure of Hsp90. These include the N-terminal domain, responsible for ATP-binding, a proteolytically resistant core domain, and the Cterminal domain that facilitates homodimerization (Fig. 1a) [9]. In eukaryotes, a more variable charged region links the N-terminal domain to the core domain. The length and composition of this linker region is highly divergent among organisms [10]. As no atomic resolution structure for full-length Hsp90 is yet available, the most thorough structural analyses for Hsp90, to date, have been based on crystallographic studies of its individual domains.A mechanistic understanding of Hsp90 was nebulous until partial sequence homology was recognized between its N-terminal domain and two types of ATP-dependent proteins. These

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Heat shock proteins in cancer: chaperones of tumorigenesis

Cited by 861 publications

References 86 publications

Immunohistochemical analysis of possible chemoresistance markers identified by micro-arrays on serous ovarian carcinomas

Immunohistochemical analysis of possible chemoresistance markers identified by micro-arrays on serous ovarian carcinomas

Key cell signaling pathways modulated by zerumbone: Role in the prevention and treatment of cancer

Hsp90—From signal transduction to cell transformation

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