Apelin-13 induces autophagy in hepatoma HepG2 cells through ERK1/2 signaling pathway-dependent upregulation of Beclin1

Abstract

Abstract. The aim of the present study was to investigate the effect of Apelin-13 on autophagy in hepatocellular carcinoma HepG2 cells and the underlying mechanism of the effect. The HepG2 cells were treated with Apelin-13 at a final concentration of 0.0001, 0.001, 0.01 and 0.1 µmol/l for 24 h. Cells were also treated with 10 µmol/l PD98059 for 24 h. The expression of the extracellular signal-regulated kinase (ERK)1/2, phosphorylated ERK1/2 (pERK1/2) and Beclin1 proteins were detected by western blot analysis. Beclin1 mRNA expression was also detected by reverse transcription-polymerase chain reaction. Autophagy was observed using fluorescence microscopy subsequent to monodansylcadaverine (MDC) staining. Following treatment with the various concentrations of Apelin-13, the expression of the ERK1/2 protein remained at a similar level, whereas the expression of pERK1/2 increased in a dose-dependent manner. Compared with the control group, the increase was significant (P<0.05). Similarly, Beclin1 expression was upregulated at the protein and mRNA levels by Apelin-13 treatment in a dose-dependent manner and was significantly increased compared with the control group. However, following treatment with the Apelin-13 inhibitor PD98059, the expression of pERK1/2, Beclin1 protein and Beclin1 mRNA were significantly decreased (P<0.05). In addition, Apelin-13 induced the autophagy of HepG2 cells in a dose-dependent manner, as revealed by MDC staining. PD98059 inhibited autophagy of HepG2 cells induced by Apelin-13. Therefore, Apelin-13 may promote autophagy in HepG2 cells by inducing the phosphorylation of ERK1/2 and upregulating the expression of Beclin1.

Triptolide induces autophagy and apoptosis through ERK activation in human breast cancer MCF‑7 cells

“…Studies have found that phosphorylation of Erk induces autophagy in human cervical cancer Hela cells (31) and liver cancer cells (22). We found that 40 nmol/l TPI could increase p-p38 MAPK and p-Erk expression after treatment for 24 h. Erk activation is closely related to autophagy induction (16,30,32).…”

“…Autophagy is a conserved process aimed at maintaining cell homeostasis under normal and stress conditions (22). Above experiments showed that TPI induced MCF-7 cell apoptosis by Bax upregulation, as well as cleaved caspase-3 activation, which indicates that TPI induces cytotoxicity through the mitochondrial pathway.…”

Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells

“…In mammalian cells, BECN1 functions as part of a class III phosphatidylinositol 3-kinase, thus participating in the generation of phosphatidylinositol-3-phosphate, which is of critical significance in autophagy modulation [60]. Huang et al [61] recently demonstrated that the APLN (apelin) active peptide APLN13 induces autophagy in hepatoma HepG2 cells through a MAPK1/ERK2 signaling pathway-dependent upregulation of BECN1. Moreover, Shrivastava et al [62] reported that hepatitis C virus upregulates BECN1 for induction of autophagy and activates MTOR signaling.…”

Molecular Association of Glia Maturation Factor with the Autophagic Machinery in Rat Dopaminergic Neurons: a Role for Endoplasmic Reticulum Stress and MAPK Activation

“…During stress conditions, the kinase mTOR is a critical regulator of autophagy induction. Phosphorylation of mTOR (p-mTOR expression) via ERK1/2 signaling regulates autophagic flux [71–73]. Increasing evidence suggests that phosphorylation of ERK1/2 activates mTOR complexes by phosphorylation of mTOR [74].…”

“…This indicates that GMF interferes with the autophagy pathway by enhancing p-mTOR expression. In addition, expression of ERK1/2 modulates the mTOR expression via phosphorylation of mTOR [74,52,73]. …”