analysis demonstrated that AMPK activity, reflected by the levels of phospho AMPK and phospho ACC, was significantly elevated in all stable, AMPK B1 overe pressing, A2780cp and SKOV3 clones compared with the vector controls. Additionally, we found that these stable AMPK B1 clones e hibited a large reduction in the e pression of pAKT, pmTOR and pP70S6K. selleck In con trast, depletion of AMPK B1 in the OV2008 and OVCA433 clones decreased AMPK activity but increased the levels of pAKT, pmTOR and pP70S6K. Interestingly, we observed that the stable, AMPK B1 overe pressing SKOV3 clones e hibited a stronger induction of pAMPK upon treatment with metformin, indicating that increased AMPK B1 enhances AMPK ac tivity, which, in turn, reduces AKT and mTOR signaling activities.
Because the AKT and mTOR Inhibitors,Modulators,Libraries signaling pathways have been widely reported to be associated with cancer cell growth, an increase in AMPK accompanied with a re duction in AKT and mTOR would no doubt inhibit cell growth and the anchorage independent growth capacities of ovarian cancer cells. Furthermore, by using the transient transfection of AMPK B1 in A2780cp cells, we found that the activities Inhibitors,Modulators,Libraries of AKT, ERK and JNK were inhibited. However, depletion of AMPK B1 in OV2008 and OVCA433 cells showed opposing results in that JNK and Inhibitors,Modulators,Libraries ERK activities were elevated. Because ERK and JNK signaling are involved in cell migration invasion, the inhibition of these pathways by AMPK B1 overe pression supports the findings that enhanced e pression of AMPK B1 suppressed cell migration and invasion in ovarian cancer cells.
Taken together, our results suggest that re e pression of Inhibitors,Modulators,Libraries AMPK B1 inhibits cell proliferation and cell migration invasion in advanced ovarian cancer cells by increasing AMPK activity but reducing AKT ERK, JNK and mTOR signaling activities. Discussion AMPK is a well known energy sensor in mammalian cells. Emerging evidence has demonstrated that AMPK e erts promoting Dacomitinib and suppressing effects on tumor onco genesis depending on the cancer cell type and the timing of tumor development. Recent studies show that AMPK enhances cell survival during metabolic stress in early stage tumors or when tumor cells detach from their e tra cellular matri . However, mounting evidence also suggests that low AMPK activity usually favors high cell proliferation in numerous, advanced stage human cancers.
Yet, the underlying molecular mechanism for modulating AMPK activity mediated cell proliferation in cancers remains unclear. In this study, we report that the AMPK B1 subunit of the AMPK comple shows a pro gressive reduction in e pression level from early to ad vanced tumor stages of ovarian cancer. We found that the reduced AMPK directly B1 is consistent with the lower AMPK activity that is found in advanced stage, high grade and metastatic ovarian cancers. Using gain and loss of function strategies, we demonstrated that AMPK B1 profoundly impairs cell growth, migration and invasion capacities via activating AMPK but attenuating AK