Targeting Cdc37 Inhibits Multiple Signaling Pathways and Induces Growth Arrest in Prostate Cancer Cells

Gray, Phillip J.; Stevenson, Mary Ann; Calderwood, Stuart K.

doi:10.1158/0008-5472.can-07-3162

Cited by 91 publications

(104 citation statements)

References 40 publications

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“…Growth inhibition was correlated with decreased signaling through the anabolic ERK and Akt kinase cascades as well as reduced AR-dependent transcriptional signaling 35 (Fig 2). In addition, Cdc37 targeting inhibits HSF1 activity and Hsp70 expression, components of a common resistance pathway that mediates insensitivity to therapeutics such as Hsp90 inhibitors and proteasomal targeting agents 35,36 (Fig 2). Inactivation of Cdc37 may thus decrease cell survival through a range of pathways, permitting effective inhibition of anabolic signaling and breaking resistance to cytotoxic therapy.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…Recent studies address the feasibility of targeting Cdc37 in prostate carcinoma 15,35 . Indeed, depletion of Cdc37 in prostate cancer cell lines by RNA interference techniques leads to permanent growth inhibition both in androgen-dependent and androgen-independent cell lines 35 .…”

Section: Targeting Cdc37 In Cancermentioning

confidence: 99%

Section: Targeting Cdc37 In Cancermentioning

confidence: 99%

“…Indeed, depletion of Cdc37 in prostate cancer cell lines by RNA interference techniques leads to permanent growth inhibition both in androgen-dependent and androgen-independent cell lines 35 . Growth inhibition was correlated with decreased signaling through the anabolic ERK and Akt kinase cascades as well as reduced AR-dependent transcriptional signaling 35 (Fig 2). In addition, Cdc37 targeting inhibits HSF1 activity and Hsp70 expression, components of a common resistance pathway that mediates insensitivity to therapeutics such as Hsp90 inhibitors and proteasomal targeting agents 35,36 (Fig 2).…”

Section: Targeting Cdc37 In Cancermentioning

confidence: 99%

“…A further clue that warrants exploration is that Cdc37 is overexpressed in prostate cancer and such cancers are induced by the forced expression of Cdc37 8,14 . As AR is one of the rare non-kinase clients for Cdc37, and is essential for proliferation and differentiation of prostatic epithelium, a role for AR would fit the profile 8 .Recent studies address the feasibility of targeting Cdc37 in prostate carcinoma 15,35 . Indeed, depletion of Cdc37 in prostate cancer cell lines by RNA interference techniques leads to permanent growth inhibition both in androgen-dependent and androgen-independent cell lines 35 .…”

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Targeting the oncogene and kinome chaperone CDC37

et al. 2008

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Cdc37 is a molecular chaperone that physically stabilizes the catalytic domains found in protein kinases and is therefore a wide-spectrum regulator of protein phosphorylation. It is also an overexpressed oncogene that mediates carcinogenesis by stabilizing the compromised structures of mutant and/or overexpressed oncogenic kinases. Recent work shows that such dependency of malignant cells on elevated Cdc37 expression is a vulnerability that can be targeted in cancer by agents that deplete or inhibit Cdc37. Cdc37 is thus a candidate for broad-spectrum molecular cancer therapy.Although Cdc37 is overexpressed in a number of cancers, it is an unusual oncoprotein whose transforming character does not readily snap into place in the conventional oncogenic pathways. Instead, it is a molecular chaperone, a protein that facilitates folding/refolding of other proteins, often described as its "clients". The role of molecular chaperones in cancer was first characterized with regard to Hsp90 (for review see 5 ). Hsp90 is a facilitator of oncogenesis that stabilizes a wide range of overexpressed or mutated oncogenic proteins and permits their tumorigenic influence to arise 3,7 . Tumors thus appear to become addicted to chaperones and can be treated by withdrawing the chaperoning power of Hsp90 [4][5][6] . Cdc37 interacts with a subset of client proteins within Hsp90 complexes and plays a specialized role as primary partner in kinome maintenance 3,8,9 . This specialized property of Cdc37 fuels the acceleration of cell proliferation observed in cancer by promoting the activities of a broad array of protein kinases 1-3 . These include receptor tyrosine kinases such as EGFR and MET, non-receptor tyrosine kinases v-src and Lck, and intracellular serine/threonine kinases Raf-1, Ksr, Akt, IKK, Cdc2, Cdk2 and Cdk4. A comprehensive list of Cdc37 client kinases, including the ones listed above and others can be found at the website of Dr Didier Picard: http://www.picard.ch/downloads/Cdc37interactors.pdf. The degree of dependency of the cancer cell kinome on Cdc37 expression thus appears to be extensive and in a recent yeast screen, at least 90 % of the protein kinases examined required Cdc37 for function 10 .The defining cellular role for Cdc37, which becomes misappropriated in cancer, resides in its promotion of cell proliferation. Indeed this protein was first discovered in a yeast screen for cell division cycle proteins, hence its name 11 . Thus when mammalian tissues undergo rapid proliferation during development, the normally scarce levels of Cdc37 are rapidly expanded. Elevated levels of Hsp90/Cdc37 complexes mediate the maturation and stabilization of protein 3Correspondence to: Stuart K. Calderwood, 21-27 Burlington Ave. Rm. 553B, Boston, MA 02215, scalderw@bidmc.harvard.edu. 2 Current address: Johns Hopkins University School of Medicine, Baltimore, MD 21205Because of space limitations we were unable to cite many significant studies on Cdc37 and Hsp90. We apologize to the authors of such studies and refer to excellent pu...

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Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Section: Targeting Cdc37 In Cancermentioning

confidence: 99%

Section: Targeting Cdc37 In Cancermentioning

confidence: 99%

Section: Targeting Cdc37 In Cancermentioning

confidence: 99%

mentioning

confidence: 99%

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Targeting the oncogene and kinome chaperone CDC37

et al. 2008

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The Pivotal Role of CK2 in the Kinome‐Targeting Hsp90 Chaperone Machinery

Miyata

2013

Protein Kinase CK2

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Targeting the HSP90–CDC37–kinase chaperone cycle: A promising therapeutic strategy for cancer

Wang

Zhang

Qin

2021

Medicinal Research Reviews

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Heat shock protein 90 (HSP90) is an indispensable molecular chaperone that facilitates the maturation of numerous oncoproteins in cancer cells, including protein kinases, ribonucleoproteins, steroid hormone receptors, and transcription factors.Although over 30 HSP90 inhibitors have steadily entered clinical trials, further clinical advancement has been restricted by their limited efficacy, inevitable heat shock response, and multiple side-effects, likely induced via an ATP inhibition mechanism. Since both ATP and various co-chaperones play essential roles in the HSP90 chaperone cycle to achieve integrated function, optimal therapeutics require an understanding of the dynamic interactions among HSP90, ATP, and cochaperones. To date, continuous research has promoted the exploration of the cochaperone cell division cycle 37 (CDC37) as a kinase-specific recognizer and has shown that the HSP90-CDC37-kinase complex is particularly relevant in cancers. Indeed, disrupting the HSP90-CDC37-kinase complex, rather than totally blocking the ATP function of HSP90, is emerging as an alternative way to avoid the limitations of current inhibitors. In this review, we first briefly introduce the HSP90-CDC37-kinase cycle and present the currently available approaches for inhibitor development targeting this cycle and provide insights into selective regulation of the kinase clients of HSP90 by more directional ways.

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Targeting Cdc37 Inhibits Multiple Signaling Pathways and Induces Growth Arrest in Prostate Cancer Cells

Cited by 91 publications

References 40 publications

Targeting the oncogene and kinome chaperone CDC37

Targeting the oncogene and kinome chaperone CDC37

The Pivotal Role of CK2 in the Kinome‐Targeting Hsp90 Chaperone Machinery

Targeting the HSP90–CDC37–kinase chaperone cycle: A promising therapeutic strategy for cancer

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