Abstract
AMP-activated protein kinase (AMPK) is a key energy sensor that is involved in regulating cell metabolism. Our previous study revealed that the subunits of the heterotimeric AMPK enzyme are diversely expressed during ovarian cancer progression. However, the impact of the variable expression of these AMPK subunits in ovarian cancer oncogenesis remains obscure. Here, we provide evidence to show that reduced expression of the AMPK-β1 subunit during tumor progression is associated with the increased oncogenic capacity of advanced ovarian cancer cells. Immunohistochemical analysis revealed that AMPK-β1 levels were reduced in advanced-stage (P = 0.008), high-grade (P = 0.013) and metastatic ovarian cancers (P = 0.008). Intriguingly, down-regulation of AMPK-β1 was progressively reduced from tumor stages 1 to 3 of ovarian cancer. Functionally, enforced expression of AMPK-β1 inhibited ovarian-cancer-cell proliferation, anchorage-independent cell growth, cell migration and invasion. Conversely, depletion of AMPK-β1 by siRNA enhanced the oncogenic capacities of ovarian cancer cells, suggesting that the loss of AMPK-β1 favors the aggressiveness of ovarian cancer. Mechanistically, enforced expression of AMPK-β1 increased AMPK activity, which, in turn, induced cell-cycle arrest via inhibition of AKT/ERK signaling activity as well as impaired cell migration/invasion through the suppression of JNK signaling in ovarian cancer cells. Taken together, these findings suggest that the reduced expression of AMPK-β1 confers lower AMPK activity, which enhances the oncogenic capacity of advanced-stage ovarian cancer.
Highlights
Ovarian cancer is one of the deadliest diseases that affects females worldwide
Loss of AMPK-β1 enhances ovarian cancer cell growth and anchorage-independent growth ability Because AMPK-β1 was obviously reduced in advancedstage ovarian cancer, we investigated the effect of AM PK-β1 on ovarian cancer cell growth and anchorageindependent growth
Emerging evidence has demonstrated that AMPK exerts promoting and suppressing effects on tumor oncogenesis depending on the cancer cell type and the timing of tumor development
Summary
Ovarian cancer is one of the deadliest diseases that affects females worldwide. The high mortality of this cancer is due to its poor prognosis; most cases are diagnosed at the advanced stage with metastatic functions [1,2]. In spite of advances in treatment over the past decade, the cure rate of ovarian cancer has improved modestly [2]. Better targeted therapies and biomarkers for diagnosis or prognosis are urgently needed. Increasing evidence has shown that cancer cells display an altered metabolism; targeting abnormal cancer metabolism is a promising therapeutic approach for cancer surveillance [3,4]. The study of key regulators of cellular metabolism in cancer cells has attracted attention [5,6,7,8,9]
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