Cdc37 as a Co-chaperone to Hsp90 - The Networking of Chaperones by Co-chaperones - page 107

of kinases may require Cdc37 to a greater or lesser degree (Gray et al. 2008 ). It
has been shown that the phosphatidyl inositol—3 kinase (PI-3K) pathway plays
a key driving role in prostate carcinogenesis and that the PI-3K inhibitory path-
way, mediated through the lipid phosphatase PTEN inhibits this process (Bitting
and Armstrong 2013 ). Indeed, inactivation of PTEN leads to spontaneous prostate
carcinogenesis. It was also shown that knockdown of Cdc37 led to inhibition of
Akt, the kinase directly downstream of PI-3K as well as to inhibition of the S6
ribosomal protein, a substrate of the mTORC1 kinase complex, another enzyme
regulated downstream of PI-3K (Gray et al. 2007 ). The mTORC1 pathway has been
shown to play key roles in cancer progression by boosting the rate of translation and
permitting elevated protein synthesis in cancer cells. Other potential Cdc37 depen-
dent targets could include receptor tyrosine kinases such as EGFR and HER2/ neu
that are CDC37 clients and could also play roles in prostate cancer (Calderwood S.
K. et al. in preparation), (Lavictoire et al. 2003 ). However, as there is currently no
definitive proof for any of these pathways and other candidates such as no-receptor
tyrosine kinases of the Src family as well as mutant or over-expressed KIT, MET,
ALK and RAF could play roles.
Cdc37 and Cancer Treatment
The dependence of cancer, particularly prostate cancer cells, on Cdc37 suggests
this molecule as a potential target. This approach would have the decided advantage
of leading to multi-targeting and the potential for evasion of resistance in contrast
to targeting individual oncoproteins, in which evolution of resistance is problem-
atic. Cdc37 knockdown was shown to reduce proliferation to minimal levels in a
range of malignant cell types (Gray et al. 2008 ; Gray et al. 2007 ; Smith and Work-
man 2009 ). A natural product-based drug has recently been isolated that can disrupt
Hsp90/Cdc37 interactions. This compound Celastrol could thus be envisaged as a
potential drug for targeting Cdc37 activity in cancer (Salminen et al. 2010 ). How-
ever, this compound is lacking in specificity, was shown to directly inhibit both
IʺʺB kinase activity and the function of the proteasome and to induce HSF1 activity
(Calderwood 2013 ). No doubt future endeavors will lead to further Cdc37-targeted
drugs with higher specificity.
Roles for Cdc37 in Autophagy and Protein Aggregation
Disorders
Unsurprisingly, with its versatile role in kinase activation, Cdc37 appears to play
roles in cell pathology outside of cancer. The Hsp90-Cdc37 complex appears to
participate in the upstream activation of autophagy, one of the primary pathways