Study Of Autophagy In The Regulation Of Response To Drug Treatment In Colorectal And Gastric Cancer Cells In Vitro

Autophagy is an evolutionarily conserved and lysosome dependent protein degradation pathway, which exists in almost all cell types. It not only plays an important role in maintaining cell homeostasis, ensuring proper proliferation and differentiation, but also protects cells from metabolic stresses. It is important to understand all these biological and pathological processes which would be useful in developing anti-cancer therapies. As a tumor suppressing mechanism, macroautophagy serves as an alternative to apoptosis to eliminate transformed cells. Some drugs inhibit tumor growth only via autophagy. However, drugs inhibiting autophagy can also induce apoptosis or necrosis, which has been shown in different anti-cancer studies. Autophagy can also protect the cancer cells from starvation and death by generating nutrients in time during anti-cancer treatment and metabolic stress. In short, autophagy is a double-edged sword for cancer cells. It is important to fully understand these biological processes. As a result we could delineate the properties of anti-cancer drugs and also the behaviors of tumor cells in order to maximize the therapeutic outcomes during anti-cancer treatments. In this thesis, we investigated the role and mechanisms of autophagy in tumorigenesis in vitro. This would provide a theoretical background and evidence for autophagy in cancer biology and its clinical applications in future human studies.Hydrogen sulfide (H2S), a gas derived from bacterial, reaches a high level in the large intestine. However, the effect of H2S in the colon cancer remains unknown. In our studies, we demonstrated for the first time that H2S could induce autophagy in colon cancer cells, which might contribute to the anti-proliferative action in cancer cells. These results not only partly elucidate the role of H2S in colon carcinogenesis, but also indicate that this gaseous compound might have therapeutic value in the treatment of colon cancer. In the second study, we demonstrated bafilomycin A1, a vacuolar H+-ATPase inhibitor, suppressed macroautophagy by preventing acidification of lysosomes in colon cancer cells. Inhition of macroautophagy by this drug lowered G1-S transition and induced apoptosis in colon cancer cells. The current results not only indicate that inhibitors of macroautophagy may be used therapeutically to inhibit cancer growth, but also delineate the relationship between macroautophagy and apoptosis. In the third experiment, we found that glucose deprivation could induce apoptosis and necrosis in gastric cancer cells which were possibly acting through autophagy inhibition. However, under the deprivation of serum but with normal glucose supply in the culture medium cancer cells could survive and proliferate possibly through activation of autophagy. From these sutides it is likely that gastric cancer cells are more sensitive to glucose deprivation when compared to normal cells. In this respect the difference between normal and cancer cells in response to glucose depletion in the growing environment may provide a clue for developing more effective anti-cancer strategy in gastric cancer patients. To conclude, we not only address the therapeutic value of three different anti-cancer approaches(as monitoring glucose in the medium is not a drug, I would not put THREE drugs in the abstract), but also elucidate the potential importance of autophagy in the cancer research and clinical oncology.