Browsing by Author "Satpathy, Minati"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    The Platelet-derived Growth Factor Receptor α Is Destabilized by Geldanamycins in Cancer Cells
    (American Society for Biochemistry and Molecular Biology, 2007-01-05) Matei, Daniela; Satpathy, Minati; Cao, Liyun; Lai, Yi-Chun; Nakshatri, Harikrishna; Donner, David B.
    The heat shock protein HSP90 serves as a chaperone for receptor protein kinases, steroid receptors, and other intracellular signaling molecules. Targeting HSP90 with ansamycin antibiotics disrupts the normal processing of clients of the HSP90 complex. The platelet-derived growth factor receptor α (PDGFRα) is a tyrosine kinase receptor up-regulated and activated in several malignancies. Here we show that the PDGFRα forms a complex with HSP90 and the co-chaperone cdc37 in ovarian, glioblastoma, and lung cancer cells. Treatment of cancer cell lines expressing the PDGFRα with the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) promotes degradation of the receptor. Likewise, phospho-Akt, a downstream target, is degraded after treatment with 17-AAG. In contrast, PDGFRα expression is not affected by 17-AAG in normal human smooth muscle cells or 3T3 fibroblasts. PDGFRα degradation by 17-AAG is inhibited by the proteasome inhibitor MG132. High molecular weight, ubiquitinated forms of the receptor are detected in cells treated with 17-AAG and MG132. Degradation of the receptor is also inhibited by a specific neutralizing antibody to the PDGFRα but not by a neutralizing antibody to PDGF or by imatinib mesylate (Gleevec). Ultimately, PDGFRα-mediated cell proliferation is inhibited by 17-AAG. These results show that 17-AAG promotes PDGFRα degradation selectively in transformed cells. Thus, not only mutated tyrosine kinases but also overexpressed receptors in cancer cells can be targeted by 17-AAG.
  • Thumbnail Image
    Item
    Tissue transglutaminase protects epithelial ovarian cancer cells from cisplatin-induced apoptosis by promoting cell survival signaling
    (Oxford University Press, 2008-10) Cao, Liyun; Petrusca, Daniela N.; Satpathy, Minati; Nakshatri, Harikrishna; Petrache, Irina; Matei, Daniela
    Tissue transglutaminase (TG2), an enzyme involved in protein cross-linking and overexpressed in ovarian tumors, has antiapoptotic effects in cancer cells and may play a role in response to chemotherapy. In this study, we investigated the role of TG2 in the sensitivity of ovarian cancer cells to cisplatin. By using stable knockdown and overexpression strategies, we demonstrate that the level of expression of TG2 regulates apoptosis induced by cisplatin in SKOV3 and OV-90 ovarian cancer cells. Interestingly, not only TG2 knockdown but also a TG2 enzymatic inhibitor (KCC009) sensitized SKOV3 cells to cisplatin. To understand the mechanism by which TG2 exerts its antiapoptotic role, we examined the effects of protein kinase B (Akt) and nuclear factor-kappa B (NF-κB), two survival pathways commonly involved in development of drug resistance. Overexpression of the constitutively active p65 subunit of NF-κB, but not constitutively active Akt, rescued cells with diminished TG2 expression from cisplatin-induced apoptosis. This implicates activation of NF-κB as the main cisplatin resistance mechanism downstream of TG2. Indeed, NF-κB activity is decreased and the level of the inhibitory subunit IκBα is increased in ovarian cancer cells engineered to express diminished levels of TG2 or treated with the enzymatic inhibitor, KCC009. Our data show that TG2 prevents apoptosis induced by cisplatin by activating the NF-κB survival pathway in ovarian cancer cells.