Studies on the mechanism involving microenvironment tolerance and autophagy in tumour

• Main Authors: Chun-Li Lin, 林峻立
• Other Authors: Rong-Tsun Wu
• Format: Others
• Language: zh-TW
• Published: 2008
• Online Access: http://ndltd.ncl.edu.tw/handle/29019751164107796679

碩士 === 國立陽明大學 === 生物藥學研究所 === 96 === Autophagy is a process in which subcellular membranes undergo dynamic morphological changes that lead to the degradation of cellular proteins and cytoplasmic organelles. This process is an important cellular response to stress or starvation. Many studies have shed light on the importance of autophagy in cancer, but it is still unclear whether autophagy suppresses tumorigenesis or provides cancer cells with a rescue mechanism under unfavorable conditions. Here we demonstrated that autophagy played a protective role and prolonged cell survival in response to therapy. Inhibition of autophagy through knockdown of autophagy gene becn1 with shRNA rendered cells vulnerable to metabolic stress and reduced cell growth rate and tumorigenicity. Autophagy protected cells from 5-fluorouracil (5-FU) induced reproductive cell death which accounted for the rebound effect after chronic exposure to 5-FU. The mechanisms underlay the protection of autophagy is independent of multidrug resistance and premature senescence. Autophagy reduced starvation and 5-FU induced reactive oxygen species production and preserved mitochondria activity. Combination treatment of autophagy inhibitors 3-methyladenine (3-MA), hydroxychloroquine (HCQ) or monensin reduced the rebound effect of 5-FU and sensitized cells to 5-FU under metabolic stress. Autophagy inhibitors were effective against multicellular resistance and synergized with other chemotherapeutic agents under various tumour microenvironmental factors in BNL and CT26 cells. These studies provide evidence that autophagy serves as a survival pathway in tumor cells treated with apoptosis activators and a rationale for the use of autophagy inhibitors alone or in combination with therapies designed to induce apoptosis in human cancers.