Altered ErbB Receptor Signaling and Gene Expression in Cisplatin-Resistant Ovarian Cancer

Abstract

The majority of ovarian cancer patients are treated with platinum-based chemotherapy, but the emergence of resistance to such chemotherapy severely limits its overall effectiveness. We have shown that development of resistance to this treatment can modify cell signaling responses in a model system wherein cisplatin treatment has altered cell responsiveness to ligands of the erbB receptor family. A cisplatinresistant ovarian carcinoma cell line PE01 CDDP was derived from the parent PE01 line by exposure to increasing concentrations of cisplatin, eventually obtaining a 20-fold level of resistance. Whereas PE01 cells were growth stimulated by the erbB receptor-activating ligands, such as transforming growth factor-A (TGFA), NRG1A, and NRG1B, the PE01 CDDP line was growth inhibited by TGFA and NRG1B but unaffected by NRG1A. TGFA increased apoptosis in PE01 CDDP cells but decreased apoptosis in PE01 cells. Differences in extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling were also found, which may be implicated in the altered cell response to ligands. Microarray analysis revealed 51 genes whose mRNA increased by at least 2-fold in PE01 CDDP cells relative to PE01 (including FRA1, ETV4, MCM2, AXL, MT3, TRAP1, and FANCG), whereas 36 genes (including IGFBP3, TRAM1, and KRT4 and KRT19) decreased by a similar amount. Differential display reverse transcriptase-PCR identified altered mRNA expression for TCP1, SLP1, proliferating cell nuclear antigen, and ZXDA. Small interfering RNA inhibition of FRA1, TCP1, and MCM2 expression was associated with reduced growth and FRA1 inhibition with enhanced cisplatin sensitivity. Altered expression of these genes by cytotoxic exposure may provide survival advantages to cells including deregulation of signaling pathways, which may be critical in the development of drug resistance. (Cancer Res 2005; 65(15): 6789-800)

The Role of Pea3 Group Transcription Factors in Esophageal Squamous Cell Carcinoma

“…51 cGMP-dependent protein kinase protects cells against oxidative stress via up-regulation of thioredoxin in a Pea3 binding site-dependent manner. 52 On the other hand, Pea3 is required for apoptosis induced by ␥-linolenic acid 53 and etoposide.…”

Rho/ROCK and MEK/ERK activation by transforming growth factor-α induces articular cartilage degradation

“…8 TGFa is a member of the epidermal growth factor (EGF) family of ligands and is well characterized for its roles in inflammatory responses to infection, epithelial maintenance and malignancies. [9][10][11] Our further investigations determined that TGFa inhibits anabolic and promotes catabolic processes in articular cartilage. 8 Thus, interference with TGFa signaling in chondrocytes represents a potential therapeutic strategy for OA.…”

Molecular mechanisms of cisplatin resistance

“…The former include autophagy, an evolutionary conserved catabolic pathway that involves the sequestration and lysosomal degradation of organelles and portions of the cytoplasm (Kroemer et al, 2010), and the heat-shock response, the integrated reaction of cells to high temperatures as well as to a plethora of stressful conditions that affect protein folding (Yamamoto et al, 2001;Macleod et al, 2005;Donnelly and Blagg, 2008). Both ovarian and NSCLC cells have been shown to progressively acquire cisplatin resistance while upregulating components of the autophagic Abbreviations: CDDP, cisplatin; DYRK1B, dual-specificity Y-phosphorylation-regulated kinase 1B; EGFR, epidermal growth factor receptor; ESCC, esophageal squamous cell carcinoma; HSPs, heat-shock proteins; NSCLC, non-small cell lung cancer; PI3K, phosphoinositide-3-kinase; ROS, reactive oxygen species.…”