Abstract
Metastasis is regarded as the fatal hallmark for colon cancer, but molecular mechanisms responsible for it have remained poorly defined. Glucocorticoid receptor (GR) within the tumor microenvironment mediates the effects of stress hormones which are used in clinics for their inflammation-modulatory and immunosuppressive properties. Further, epigenetic activation of GR promotes tumor heterogeneity and metastasis. Here, we sought to investigate the correlation between GR activation and proliferation and invasion in metastatic colon cancer microenvironment. We used proliferation/invasion assays, western blot, RT-qPCR, immunofluorescence staining and quantitative methylation to study glucocorticoid-GR signaling, including the involvement of CDK1, in human colon adenocarcinoma cell lines HT29 and T84 (a representative metastatic cell line). Nuclear expression levels of GR were significantly upregulated in metastatic T84 cells, and glucocorticoid derivative, dexamethasone (DEX) treatment caused increased proliferation and invasion in T84 cell, compared to HT29 cell. DEX treatment induced CDK1 expression which was accompanied by reduced CDK1 methylation, indicating epigenetic regulation. Depletion of GR suppressed proliferation of metastatic colon carcinoma cells and depletion of CDK1 had similar suppressing effects on proliferation as well as invasion of metastatic cells. Our study suggests that glucocorticoid-GR-CDK1 signaling induces proliferation and invasion of colon cancer cells and therapies involving the use of glucocorticoids need to exercise caution and re-evaluation.
Highlights
Colorectal cancer (CRC) is one major cancer that results in numerous cancer-related deaths around the world[1,2]
We show that treatment of metastatic human colon carcinoma cell line, T84 with dexamethasone (DEX), a potent synthetic glucocorticoid, which is reminiscent of signaling within the tumor microenvironment, led to enhanced proliferation as well as invasion, compared to non-metastatic CRC cell line, HT29
These results suggest that Glucocorticoid receptor (GR) is constitutively activated in metastatic colon carcinoma cells at a higher rate than the non-metastatic colon carcinoma cells
Summary
Colorectal cancer (CRC) is one major cancer that results in numerous cancer-related deaths around the world[1,2]. Our primary hypothesis for this study was that glucocorticoid-GR signaling promotes cell proliferation in metastatic CRC. We show that treatment of metastatic human colon carcinoma cell line, T84 with dexamethasone (DEX), a potent synthetic glucocorticoid, which is reminiscent of signaling within the tumor microenvironment, led to enhanced proliferation as well as invasion, compared to non-metastatic CRC cell line, HT29. In order to determine whether GR is activated in colon cancer, we performed western blotting analysis on extracts (nuclear and cytosolic) prepared from HT29 or T84 cell.
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