Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells

Abstract

Drug resistance in cancer cells involves complex molecular mechanisms and ovarian carcinoma cells become resistant to chlorambucil (Cbl) after continuous treatment. This drug-and ionizing radiation-resistant cells have lower level of endogenous ROS (reactive oxygen species) compared with sensitive cells. Elevation of the cellular ROS level by exogenous ROS generation increases the sensitivity of Cbl to resistant cells. In contrast, antioxidants prevent the sensitization of resistant cells to Cbl by H 2 O 2 , COS (chronic oxidative stress) or NOO À . The molecular mechanism of drug sensitivity with COS has been investigated by microarray gene expressions followed by gene network analysis and it reveals that a cdc42/rac1 guanine exchange factor, ARHGEF6, with p53 and DNA-Pkc (PRKDC) is central to induce apoptosis in Cbl cos (Cbl with COS) cells. mRNA and protein levels of major gene network pathway differ significantly in Cbl cos cells than in Cbltreated cells. Moreover, DNA-PKc physically interacts with ARHGEF6 and p53 mostly in the nucleus of Cbl-treated cells, whereas in Cbl cos -treated cells, its interactions are mostly in the cytoplasm. These results suggest that low doses of Cbl and very low doses of COS together kill Cbl-resistant ovarian carcinoma cells and ARHGEF6 signaling may have an instrumental role in induction of apoptosis in Cbl cos cells.

Defects in the Fanconi Anemia Pathway in Head and Neck Cancer Cells Stimulate Tumor Cell Invasion through DNA-PK and Rac1 Signaling

“…Further analysis identified a novel link between DNA-PKcs and Rac1 signaling in FA HNSCC cells wherein a specific DNA-PK inhibitor decreased active Rac1-GTP protein levels. One possible mechanism might be supported by a previous finding that DNA-PKcs can physically interact with the CDC42/Rac1 guanine exchange factor, ARHGEF6, in ovarian cancer cells (42). In addition, growing evidence supports correlations between DNA damage signaling and Rac1 activity (43–45), although the mechanisms and functional relevance of pathway cross-talk are largely unclear.…”

Distinct Subpopulations of Head and Neck Cancer Cells with Different Levels of Intracellular Reactive Oxygen Species Exhibit Diverse Stemness, Proliferation, and Chemosensitivity

“…Most of the anticancer drugs kill cancer cells by induced ROS generation, but prolonged treatment with the drugs results in reduced ROS level as a result of therapy resistance (38,39). Caraglia and colleagues (40) provide evidence that the determination of oxidative stress status could be a marker of drug efficacy in patients with cancer.…”

Hepatic Gene Networks in Morbidly Obese Patients With Nonalcoholic Fatty Liver Disease

“…The normalized phenotypes were comparable between individuals and across transcripts. Current microarrays allow accurate detection of gene transcripts that correlate well with real-time PCR as shown in many studies [11,20,21,26,27]. Furthermore, the high heritability of housekeeping gene transcripts traditionally used in RT-PCR validation (e.g., heritability for B-actin expression is 0.373, p1:0 Â 10 À9 , and for cyclophilin-D is 0.559, p1:0 Â 10 À9 ) [28] make them less than ideal as references for internal standardization.…”