Molecular and cellular pathways in colorectal cancer: apoptosis, autophagy and inflammation as key players.

BACKGROUND: Colorectal carcinogenesis (CRC) is one of the most aggressive forms of cancer, particularly in developing countries. It accounts for the second and third-highest reason for cancer-induced lethality in women and men respectively. CRC involves genetic and epigenetic modifications in colonic epithelium, leading to colon adenocarcinoma. The current review highlights the pathogenic mechanisms and multifactorial etiology of CRC, influenced by apoptosis, inflammation, and autophagy pathways. METHODS: We have carried out a selective literature review on mechanisms contributing to the pathogenesis of CRC. RESULTS: Resistance to senescence and apoptosis of the mesenchymal cells, which play a key role in intestinal organogenesis, morphogenesis and homeostasis, appears important for sporadic CRC. Additionally, inflammation-associated tumorigenesis is a key incident in CRC, supported by immune disruptors, adaptive and innate immune traits, environmental factors, etc. involving oxidative stress, DNA damage and epigenetic modulations. The self-digesting mechanism, autophagy, also plays a twin role in CRC through the participation of LC3/LC3-II, Beclin-1, ATG5, other autophagy proteins, and Inflammatory Bowel Disease (IBD) susceptibility genes. It facilitates the promotion of effective surveillance pathways and stimulates the generation of malignant tumor cells. The autophagy and apoptotic pathways undergo synergistic or antagonistic interactions in CRC and bear a critical association with IBD that results from the pro-neoplastic effects of persistent intestinal inflammation. Conversely, pro-inflammatory factors stimulate tumor growth and angiogenesis and inhibit apoptosis, suppressing anti-tumor activities. CONCLUSION: Hence, research attempts for the development of potential therapies for CRC are in progress, primarily based on combinatorial approaches targeting apoptosis, inflammation, and autophagy.

Inhibiting endoplasmic reticulum stress mediated-autophagy enhances the pro-apoptotic effects of resveratrol derivative in colon cancer cells.

Previous studies have demonstrated that endoplasmic reticulum stress (ERS) might play a major role in inducing cellular autophagy and apoptosis in multiple types of cancer. Herein, we observed that trans-3,5,4'-trimethoxystilbene (TMS) exposure facilitated apoptotic cell death and ERS-mediated autophagy in colon cancer SW480 and HCT116 cells. Interestingly, our data demonstrated that ERS was not involved in TMS-induced apoptosis. However, ERS notably induced protective autophagy in SW480 and HCT116 cells. In addition, inhibiting cellular ERS significantly improved the pro-apoptotic effects of TMS. Thus, our results indicated that TMS-mediated autophagy was dependent on ERS, while apoptotic cell death might be induced in the ERS-independent pathway after TMS treatment. Generally, inhibiting ERS-mediated autophagy can enhance the pro-apoptotic effects of TMS. TMS might be a potential therapeutic agent for colon cancer treatment.