Hsp27 blockade selectively inhibits growth of tumors with an activated PI3K pathway by regulating Akt and PEA-15

3553 Hsp27 is a cytoprotective chaperone that is over-expressed in a wide range of malignancies and is associated with poor prognosis and therapeutic resistance. OGX-427, a selective inhibitor of Hsp27 expression has recently entered Phase I clinical trials for treatment of patients with prostate, breast, ovarian and lung cancers. Here we show that Hsp27 blockade selectively inhibits growth of cancer cells with an activated PI3K pathway and the Hsp27 chaperone is required for Akt stability and activity that, in turn, regulates phosphorylation and function of PEA-15. Hsp27 induces dual coordinated effects resulting in protection from Fas-induced apoptosis and promotion of cell proliferation through regulation of PEA-15 phosphorylation and function in an Akt dependent manner. Hsp27 overexpression induced activation of Akt and increased phosphorylation of its downstream target PEA15 resulting in enhanced ERK translocation to nucleus and increased Elk-1 activity which correlated with increased cyclin D1 and CDK2 expression with a concomitant decrease in p27kip1 expression and increased cell proliferation. Furthermore, Hsp27 overexpression also led to increased association of PEA-15 with FADD and decreased sensitivity of cells to Fas-induced apoptosis . Conversely, Hsp27 knockdown led to reduced Akt activity and decreased phosphorylation of PEA-15 leading to reduced association of PEA-15 with FADD and increased sensitivity of cells to Fas induced apoptosis. Significantly, siRNA mediated Hsp27 knockdown in a panel of cell lines and in PTEN Tet-ON LNCaP cells that express PTEN in a doxycycline inducible manner demonstrated selective inhibition of growth of cancer cells that have an activated PI3K pathway. Collectively, these data identify a dual role of Hsp27 in regulating cell proliferation and Fas-induced apoptosis through regulation of Akt and PEA-15 and suggest that improved clinical responsiveness to Hsp27 targeted therapy may be achieved by stratifying patient populations based on the dependence of cancer cells on the PI3K pathway.