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Methylseleninic acid sensitizes Notch3-activated OVCA429 ovarian cancer cells to carboplatin.

ABSTRACT: Ovarian cancer, the deadliest of gynecologic cancers, is usually not diagnosed until advanced stages. Although carboplatin has been popular for treating ovarian cancer for decades, patients eventually develop resistance to this platinum-containing drug. Expression of neurogenic locus notch homolog 3 (Notch3) is associated with chemoresistance and poor overall survival in ovarian cancer patients. Overexpression of NICD3 (the constitutively active form of Notch3) in OVCA429 ovarian cancer cells (OVCA429/NICD3) renders them resistance to carboplatin treatment compared to OVCA429/pCEG cells expressing an empty vector. We have previously shown that methylseleninic acid (MSeA) induces oxidative stress and activates ataxia-telangiectasia mutated and DNA-dependent protein kinase in cancer cells. Here we tested the hypothesis that MSeA and carboplatin exerted a synthetic lethal effect on OVCA429/NICD3 cells. Co-treatment with MSeA synergistically sensitized OVCA429/NICD3 but not OVCA429/pCEG cells to the killing by carboplatin. This synergism was associated with a cell cycle exit at the G2/M phase and the induction of NICD3 target gene HES1. Treatment of N-acetyl cysteine or inhibitors of the above two kinases did not directly impact on the synergism in OVCA429/NICD3 cells. Taken together, these results suggest that the efficacy of carboplatin in the treatment of high grade ovarian carcinoma can be enhanced by a combinational therapy with MSeA.

SUBMITTER: Tzeng TJ

PROVIDER: S-EPMC4092030 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Methylseleninic acid sensitizes Notch3-activated OVCA429 ovarian cancer cells to carboplatin.

Tzeng Tiffany J TJ Cao Lei L Fu YangXin Y Zeng Huawei H Cheng Wen-Hsing WH

PloS one 20140710 7

Ovarian cancer, the deadliest of gynecologic cancers, is usually not diagnosed until advanced stages. Although carboplatin has been popular for treating ovarian cancer for decades, patients eventually develop resistance to this platinum-containing drug. Expression of neurogenic locus notch homolog 3 (Notch3) is associated with chemoresistance and poor overall survival in ovarian cancer patients. Overexpression of NICD3 (the constitutively active form of Notch3) in OVCA429 ovarian cancer cells (O ...[more]

PMID: 25010594

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Project description:Distinctive genotypic and phenotypic features of ovarian cancer via epithelial-mesenchymal transition (EMT) have been correlated with drug resistance and disease recurrence. We investigated whether therapeutic reversal of EMT could re-sensitize ovarian cancer cells (OCCs) to existing chemotherapy. We report that epimorphin, a morphogenic protein, has pivotal control over mesenchymal versus epithelial cell lineage decision of the putative OCCs. Exposure to epimorphin induced morphological changes reminiscent of mesenchymal-to-epithelial transition (MET), but in a dose dependent manner, i.e., at 10 µg/mL of epimorphin cells obtain a more mesenchymal-like morphology while at 20 µg/mL of epimorphin cells display an epithelial morphology. The latter changes were accompanied by suppression of mesenchymal markers, such as vimentin (?8-fold?, p<0.02), Twist1 (?7-fold?, p<0.03), dystroglycan (?4-fold?, p<0.01) and palladin (?3-fold?, p<0.01). Conversely, significant elevations of KLF4 (?28-fold?, p<0.002), ?-catenin (?6-fold?, p<0.004), EpCAM (?6-fold?, p<0.0002) and occludin (?15-fold?, p<0.004) mRNAs as part of the commitment to the epithelial cell lineage were detected in response to 20 µg/mL of exogenous epimorphin. Changes in occludin mRNA levels were accompanied by a parallel, albeit weaker expression at the protein level (?5-fold?, p<0.001). Likewise, acquisition of epithelial-like properties, including mucin1, CK19, and ?-catenin gene expression, was also obtained following epimorphin treatment. Further, MMP3 production was found to be reduced whereas laminin secretion was strongly amplified upon epimorphin-induced MET. These results suggest there is a dosage window for actions of epimorphin on cellular differentiation, wherein it can either suppress or enhance epithelial differentiation of OCCs. Importantly, induction of epithelial-like phenotypes by epimorphin led to an enhanced sensitivity to carboplatin. Overall, we demonstrate that epimorphin can revert OCCs away from their mesenchymal phenotype and toward an epithelial phenotype, thereby enhancing their sensitivity to a front-line chemotherapeutic agent.

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Methylseleninic acid sensitizes Notch3-activated OVCA429 ovarian cancer cells to carboplatin.

Publications

Methylseleninic acid sensitizes Notch3-activated OVCA429 ovarian cancer cells to carboplatin.

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