The working hypothesis of our laboratory focuses on the convergence of prosurvival, angiogenesis and motility signals at common pathways in the local tumor microenvironment for therapeutic targeting and monitoring. We continue to study two pathways we have identified: the BAG-3 stress co-chaperone protein and the ovarian cancer growth and survival factor, progranulin (pgrn). We are now reporting that BAG3 is a selective survival protein for those pathways in which HSP70 is involved. It is tightly regulated in the cell by both caspase cleavage and proteosomal degradation. We will initiate studies of the role of BAG3 and its binding partner, Hsp27, identified through the NCI/Myriad yeast two hybrid contract, to identify the role of this interaction in protection of BAG3. BAG3/Hsp27 binding is confirmed. We previously reported increased migration in cells overexpressing select domain mutants. We completed and published documentation that CCN1, a matricellular signaling protein, is induced indirectly in BAG3-associated migration and further showed that this interaction occurred in several cellular backgrounds. CCN1 was upregulated in the more adhesive and migratory cells. Currently, we are advancing the dissection of BAG3 related invasion through study of differentially regulated miRNAs. We continue to analyze functional effects of BAG3 through two in vivo models: Drosophila and transgenic expression. Expression of our Drosophila homolog of BAG 3/4, evil, has been successfully overexpressed and neutralized in vivo yielding complementary phenotypes fulfilling our survival hypothesis. Characterization continues in collaboration with Dr. Sandstrom of NIMH. MMTV-BAG3 mice have been generated and propagated;a DMBA carcinogenesis experiment is maturing at this writing. We reported that pgrn is a growth and survival factor for ovarian cancer. We have demonstrated that secretory leukocyte protease inhibitory (SLPI) is a pgrn partner protein and is necessary for ovarian cancer cells survival. We have shown that SLPI protects pgrn from elastase cleavage and upregulation of SLPI is associated with greater tumor dissemination in vivo. This dissemination is independent of loss of protease inhibition function and is associated with altered regulation of a pro-invasion protease. SLPI and protease expression colocalize in serous ovarian cancer tissues, but not with endometrioid ovarian cancers. Further analysis of the mechanisms of altered protease secretion are underway. We have also shown that SLPI can overcome the anti-cancer effect of paclitaxel and a neutralizing anti-SLPI may be a new therapeutic direction. Thus, the pgrn/SLPI axis and BAG3 have potential as molecular therapeutic targets in ovarian cancer and other solid tumors.
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