Critical Role of AMPK/FoxO3A Axis in Globular Adiponectin‐Induced Cell Cycle Arrest and Apoptosis in Cancer Cells

Abstract

Adiponectin predominantly secreted from adipose tissue has exhibited potent anti-proliferative properties in cancer cells via modulating cell cycle and apoptosis. FoxO3A, a Forkhead box O member of the transcription factor, plays a critical role in modulating expression of genes involved in cell death and/or survival. In this study, we investigated the role of FoxO3A signaling in anti-cancer activities of adiponectin. Herein, we have shown that treatment with globular adiponectin (gAcrp) increases p27 but decreases cyclinD1 expression in human hepatoma (HepG2) and breast (MCF-7) cancer cells. Gene ablation of FoxO3A prevented gAcrp-induced increase in p27 and decreased in cyclin D1 expression, and further ameliorated cell cycle arrest by gAcrp, indicating a critical role of FoxO3A in gAcrp-induced cell cycle arrest of cancer cells. Moreover, treatment with gAcrp also induced caspase-3/7 activation and increased Fas ligand (FasL) expression in both HepG2 and MCF-7 cells. Transfection with FoxO3A siRNA inhibited gAcrp-induced caspase-3/7 activation and FasL expression, suggesting that FoxO3A signaling also plays an important role in gAcrp-induced apoptosis of cancer cells. We also found that gene silencing of AMPK prevented gAcrp-induced nuclear translocation of FoxO3A in HepG2 and MCF-7 cells. In addition, suppression of AMPK also blocked gAcrp-induced cell cycle arrest and further attenuated gAcrp-induced caspase-3/7 activation, indicating that AMPK signaling plays a pivotal role in both gAcrp-induced cell cycle arrest and apoptosis via acting as an upstream signaling of FoxO3A. Taken together, our findings demonstrated that AMPK/FoxO3A axis plays a cardinal role in anti-proliferative effect of adiponectin in cancer cells.

Casticin suppresses the carcinogenesis of small cell lung cancer H446 cells through activation of AMPK/FoxO3a signaling

“…Given that casticin suppresses cell growth in ovarian cancer (SKOV3) cells through FOXO3a activation (13), we aimed to ascertain whether casticin inhibits in vitro carcinogenesis and CSC characteristics in SCLC LCSLCs by activating FOXO3a, a transcription factor inactivated by AMPK (14)(15)(16)24). We first found that casticin significantly increased the phosphorylation levels of AMPK and ACC, in a concentration-dependent manner.…”

“…Yung et al (9) demonstrated that AMPK activation inhibited cervical cancer cell growth through AKT/FOXO3a/FOXM1 signaling. Meanwhile, Shrestha et al (14) reported that the AMPK/FoxO3A axis plays a critical role in the antiproliferative effects of adiponectin in cancer cells. Furthermore, Sato et al proposed that metformin efficaciously eliminates glioma stem cell-like cells by activating FOXO3 via AMPK (8).…”

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

“…Further studies have suggested that the AMPK-FOXO3 signaling exerts endurable and protective impact against skeletal atrophy [119] and keratinocytic senescence [120], mainly based on its transcriptional reprogramming. Additionally, its anti-tumor functionality has also been verified in breast and liver cancer in vitro , demonstrating a remarkable growth-inhibitory effect [121]. …”

Nobiletin induces growth inhibition and apoptosis in human nasopharyngeal carcinoma C666‐1 cells through regulating PARP‐2/SIRT1/AMPK signaling pathway

“…AMPK, a key regulator of energy metabolism, is one of the substrates of SIRT1 and activated by phosphorylation (Cheng et al., ; You, Cheng, Yu, Duan, & Peng, ). Besides, AMPK is reported to be related to cell cycle and apoptosis (Shrestha et al., ). Moreover, a large number of studies have shown that multiple anticancer agents could activate AMPK‐dependent cell death pathways (An et al., ; Gao, Ge, & Sun, ).…”

“…AMPK, a key regulator of energy metabolism, is one of the substrates of SIRT1 and activated by phosphorylation You, Cheng, Yu, Duan, & Peng, 2018). Besides, AMPK is reported to be related to cell cycle and apoptosis (Shrestha et al, 2016).…”