To our knowledge, this is the first comprehensive study of AMPK B1 e pression, function and mechanism of action in human cancer cells. Recent studies have suggested that AMPK acts as a metabolic tumor suppressor due to its roles in governing the activities of mTOR, p53 and other regulatory mole cules as well as fatty acid synthesis. Hence, tumor cells must reduce the activity of AMPK to maintain their high proliferative capacity in oncogenesis. Loss of LKB1 is a well known mechanism in suppressing AMPK activity and is commonly found in lung cancer, melanoma, gastro intestinal carcinoma and dysplastic hamartoma in Peutz Jeghers syndrome. However, most human cancers with an intact LKB1 function still maintain low AMPK ac tivity when e erting their tumorigenic properties, indicating that multiple mechanisms e ist that depress AMPK activity in such cancer cells.
AMPK is a heterotri meric comple consisting of a catalytic alpha subunit and regulatory beta and gamma subunits. We previously re ported that the AMPK subunits are differentially e pressed and that different subunits have different clinical implica tions in the development of ovarian cancer. Of these subunits, we found that the mRNA level of AMPK B1 was dominantly e pressed and tightly correlated with AMPK activity when compared with AMPK B2 during the pro gression of ovarian cancer and other human cancers. Consistent with our previous findings, the IHC data in this study further demonstrates that AMPK B1 e pres sion shows a stepwise reduction from early to late stage ovarian cancer.
In addition, reduced AMPK B1 e pression shows a significant association with late stage, high grade and metastatic ovarian cancers, suggesting that reduced AMPK B1 e pression decreases AMPK activity and en hances the aggressiveness of advanced ovarian cancer. Al though the underlying molecular mechanisms Dacomitinib leading to the downregulation of AMPK B1 during ovarian cancer progression remain unknown, the recent finding of the un dere pression of AMPK 2 in liver cancer cells indi cates that DNA methylation and histone deacetylation may be involved in silencing the e pressions of AMPK subunits in ovarian cancer cells. Our results indicate that the inhibitory effect of AMPK B1 on cell growth is mediated through an increase in AMPK activation and a simultaneous decrease in AKT pathway activity.
In the AMPK heterotrimeric comple , the AMPK B subunit acts as a scaffold to support the binding of the catalytic and regulatory subunits. We postulated that AMPK B1 upregulation most likely leads to an increase in the number of AMPK heterotrimeric comple es, which, in turn, facilitates induced activation of AMPK by either microenvironemental stresses or pharmaceutical activators. In contrast, lower AMPK B1 e pression may reduce the number of AMPK heterotri meric comple es, which leads to lower AMPK activity in advanced ovarian cancers.
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