Abstract
Cysteine-rich angiogenic inducer 61 (CYR61) is an extracellular matrix-associated protein involved in survival, tumorigenesis, and drug resistance. Therefore, we examined the effects of flavones against CYR61-overexpressing human gastric adenocarcinoma AGS (AGS-cyr61) cells, which show remarkable resistance to 5-fluorouracil (5-FU), adriamycin (ADR), tamoxifen (TAM), paclitaxel (PAC), and docetaxel (DOC). Among the tested flavones, quercetin had the lowest 50% inhibitory concentration (IC50) and significantly reduced the viability of AGS-cyr61 cells compared with AGS cells. Quercetin: (1) reduced multidrug resistance-associated protein 1 and nuclear factor (NF)-kappa B p65 subunit levels; (2) reversed multidrug resistance (MDR); (3) inhibited colony formation and induced caspase-dependent apoptosis; and (4) suppressed migration and down-regulated epithelial–mesenchymal transition-related proteins in AGS-cyr61. Moreover, AGS-cyr61 cells treated with quercetin concentrations close to the IC50 and simultaneously treated with 5-FU or ADR in the sub-lethal range showed strong synergism between quercetin and these two drugs. These findings indicate that CYR61 is a potential regulator of drug resistance and that quercetin may be a novel agent for improving the efficacy of anticancer drugs in AGS-cyr61 cells.
Highlights
Gastric cancer is a major public health problem globally and the second leading cause of death from malignant tumors, with a five-year survival rate of only about 20% [1]
Because it has been reported that Cysteine-rich angiogenic inducer 61 (CYR61) is associated with PAC and ADR resistance in breast cancer cells [21], we first examined whether CYR61 is related to multidrug resistance (MDR) in gastric cancer cells
These results indicate that CYR61 overexpression confers MDR
Summary
Gastric cancer is a major public health problem globally and the second leading cause of death from malignant tumors, with a five-year survival rate of only about 20% [1]. Many lines of evidence suggest that overexpression of the CCN family (cysteine-rich protein [CYR61], connective tissue growth factor [CTGF], and nephroblastoma overexpressed gene [Nov]) increase migration, peritoneal dissemination, and carcinogenic progress in gastric cancer cells [2,3]. CYR61 was highly expressed in a more advanced gastric adenocarcinoma specimen, and the human gastric cancer cell line overexpressing CYR61 significantly increased tumor cell motility and invasion through activation of the integrin/nuclear factor-kappa B (NF-κB) p65/cyclooxygenase-2 signaling pathway. Increased CYR61 levels have been reported to induce increased proliferation and invasion [4], and induce resistance to apoptosis and paclitaxel (PAC) in breast cancer cells [5,6]. Because of the importance of chemotherapy in gastric cancer treatment, multidrug resistance (MDR) is a major obstacle to effective chemotherapy
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