Trans cinnamaldehyde enhances TRAIL induced apoptosis through ER stress mediated upregulation of DR5 in colorectal cancer cells

Trans-cinnamaldehyde (TCA), a natural compound isolated from the stem bark of Cinnamon cassia, has been recognized as a potential therapeutic agent for treating various diseases, including inflammatory conditions and diverse cancers. TNF-related apoptosis-inducing ligand (TRAIL) is known to induce apoptosis selectively in cancer cells while sparing normal cells. However, resistance to TRAIL-mediated apoptosis is a significant limitation in cancer therapy. This study aimed to investigate whether TCA could enhance the sensitivity of colorectal cancer cells to TRAIL induced apoptosis and to elucidate the underlying molecular mechanisms involved in this synergistic effect. The study was designed to evaluate the antitumor effects of TCA and TRAIL, both individually and in combination, using colorectal cancer cell lines and in vivo models. Various colorectal cancer cell lines and normal cells were treated with TCA, TRAIL, or their combination. Cell viability assays were conducted to determine the synergistic effects. Western blotting was performed to analyze the expression of ER stress-related proteins. Knockdown of DR5 or CHOP was achieved using siRNA to evaluate its role in the combined anticancer effect. in vivo experiments were conducted to confirm the antitumor effects of the TCA and TRAIL combination. We observed that the combination of TCA and TRAIL exhibits synergistic antitumor effects both in vitro and in vivo. The anticancer effect was notably enhanced when TCA and TRAIL were used to treat various colorectal cancer cell lines, but not normal cells. Additionally, the levels of endoplasmic reticulum (ER) stress-related proteins, such as phosphorylated protein kinase RNA-like ER kinase (PERK), phosphorylation of the eukaryotic initiation factor 2 (eIF2α), and C/EBP homologous protein (CHOP), increased in a dose-dependent manner when treated with TCA. Significantly, TCA elevated DR5 expression levels through ER stress. Knockdown of CHOP reduced the combined effect of TCA and TRAIL. TCA enhances TRAIL-induced apoptosis in colorectal cancer cells by inducing ER stress and upregulating DR5 expression. These findings suggest that TCA is a promising agent for overcoming TRAIL resistance and improving its therapeutic efficacy in colorectal cancer treatment.