Abstract
Though epigallocatechin-3-gallate (EGCG), a major compound of green tea, has anti-diabetes, anti-obesity, anti-inflammatory, and antitumor effects, the underlying antitumor molecular mechanism of EGCG was not fully understood so far. Here the sensitizing effect of EGCG to tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) was examined in colorectal cancers. Cotreatment of EGCG and TRAIL synergistically enhanced cytotoxicity and sub G1 accumulation, increased the number of terminal deoxynucleotidyl transferase-dT-mediated dUTP nick end labelling (TUNEL)-positive cells in SW480 and HCT116 cells. Furthermore, this cotreatment promoted the cleavages of poly (adenosine diphosphate-ribose) polymerase (PARP) and induced caspase 8 activation compared to TRAIL or EGCG alone in SW480 and HCT116 cells. Of note, cotreatment of EGCG and TRAIL increased the expression of death receptor 5 (DR5) at protein and mRNA levels and also DR5 cell surface level in colon cancer cells. Conversely, depletion of DR5 reduced the apoptotic activity of cotreatment of EGCG and TRAIL to increase cytotoxicity, sub-G1 population and PARP cleavages in colon cancer cells. Overall, our findings provide evidence that EGCG can be a sensitizer of TRAIL via DR5 and caspase 8 mediated apoptosis in colorectal cancer cells.
Highlights
Though about 70%–80% of colorectal cancer (CRC) patients have been subjected to surgical resection worldwide, approximately 40% of them have metastases or recurrence and eventually die [1].though anti-cancer agents including tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) [2] and 5-Fluorouracil [3] have been used for treatment of CRCs, their chemo-resistance and side effects have become hot issues to be overcome
To assess the cytotoxicity of EGCG and/or TRAIL, MTT assay was conducted in HT29, SW480, HCT116 cells
Western blotting revealed that cotreatment of EGCG and TRAIL enhanced the expression of death receptor 5 (DR5) at protein level but not DR4 (Figure 3A)
Summary
Though about 70%–80% of colorectal cancer (CRC) patients have been subjected to surgical resection worldwide, approximately 40% of them have metastases or recurrence and eventually die [1]. Though anti-cancer agents including tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) [2] and 5-Fluorouracil [3] have been used for treatment of CRCs, their chemo-resistance and side effects have become hot issues to be overcome. TRAIL is well known to induce apoptosis in breast [6], prostate [7], lung [8] and renal cancers [9,10] as a potent anticancer agent. Emerging evidence suggests targeting TRAIL receptor can be a good strategy for cancer therapy including chemoresistance [11,12]
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