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암 전이 과정에서 mTOR와 NAMPT의 역할 연구

Title
암 전이 과정에서 mTOR와 NAMPT의 역할 연구
Authors
홍선미
Date Issued
2013
Publisher
포항공과대학교
Abstract
Cancer cells adapt their metabolism to overcome the stressful microenvironment which causes the metabolic stress, such as hypoxia, nutrient deprivation and acidification. The alterations to cellular metabolism are important in cancer progression. The mammalian Target Of Rapamycin (mTOR) link to the nutrient availability and cell growth. mTOR signaling is dysregulated in many cancer and promotes the destructive growth of cancer. Despite emerging targets in the mammalian target of rapamycin (mTOR) pathway to treat cancer, using the mTOR pathway to treat cholangiocarcinoma (CC) has yet to be investigated. In this study, we investigate which CC cell types are susceptible to rapamycin, an mTOR inhibitor, and whether rapamycin could suppress effectively the growth and the metastatic properties in CC cell lines in vitro and in vivo. Here, we found that activation of the AKT/mTOR pathway was correlated with the different degrees of dedifferentiation in CC cell lines. In the sarcomatoid CC cell line, SCK, the Akt/mTOR pathway was more activated than in the well- or moderately-differentiated adenomatoid CC cells, such as the Cho-CK and Choi-CK cells. mTOR inhibition by rapamycin treatment caused cell cycle arrest through down-regulation of the expression of CDK2 and CDK4, which suppressed the proliferation of CC cells in vitro. In the xenograft tumor models used for the in vivo studies, rapamycin suppressed tumor growth in subcutaneous CCs, and especially in sarcomatoid SCK cells. Furthermore, inhibition of the mTOR pathway with rapamycin could suppress the motility and the peritoneal dissemination of sarcomatoid SCK cells. Rapamycin decreased significantly the number of tumor nodules and prolonged the survival rates of nude mice inoculated with sarcomatoid CC cells intraperitoneally. Prolonged treatments with rapamycin were found to disrupt the mTORC2 assembly and to reduce the phosphorylation of STAT3 at Ser 727 in SCK cells. Rapamycin decreased both mRNA and protein levels of MMP2 and Twist1, which are regulated by STAT3 and associated with cancer metastasis. The overexpression of STAT3 S727A lacking the phosphorylation site resulted in significantly less sensitivity to rapamycin than the overexpression of STAT3 WT. Taken together, our data suggest that rapamycin is a potential anticancer treatment for CCs and is especially effective in treating sarcomatoid CCs via the impairment of mTORC1 and mTORC2 assemblies. NAMPT is an enzyme of the rating-limiting step for NAD biosynthesis and is known to be induced by metabolic stress. However, the underlying mechanisms by which NAMPT alters metabolism in cancer cells are not fully established. In this study, we revealed that NAMPT induced the resistance to glucose deprivation in breast cancer cells. Breast cancer cells with high expression of NAMPT exhibited the resistance to glucose deprivation and the modulation of NAMPT expression affected the cell survival during glucose deprivation. NAMPT could not regulate the ATP depletion but the ROS generation upon glucose depletion. Glucose deprivation decreased the levels of NADPH via the impairment of pentose phosphate pathway. But NAMPT increased the levels of NADPH and prolonged cell survival by down-regulating the level of ROS during glucose deprivation. Sirt1 mediated the NAMPT-mediated the resistance to glucose deprivation. We further confirmed that 2-deoxy-D-glucose, glucose analogue, combined with FK866, NAMPT inhibitor, enhanced oxidative stress and promote cell death. Taken together, our data suggest that the roles of NAMPT in NADPH generation could be important in cancer cell survival under glucose deprivation.
URI
http://postech.dcollection.net/jsp/common/DcLoOrgPer.jsp?sItemId=000001561093
http://oasis.postech.ac.kr/handle/2014.oak/1876
Article Type
Thesis
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