EGR‑1 plays a protective role in AMPK inhibitor compound C‑induced apoptosis through ROS‑induced ERK activation in skin cancer cells

Abstract

Skin cancer is caused by abnormal proliferation, gene regulation and mutation of epidermis cells. Compound C is commonly used as an inhibitor of AMP-activated protein kinase (AMPK), which serves as an energy sensor in cells. Recently, compound C has been reported to induce apoptotic and autophagic death in various skin cancer cell lines via an AMPK-independent pathway. However, the signaling pathways activated in compound C-treated cancer cells remain unclear. The present oligodeoxynucleotide-based microarray screening assay showed that the mRNA expression of the zinc-finger transcription factor early growth response-1 (EGR-1), which helps regulate cell cycle progression and cell survival, was significantly upregulated in compound C-treated skin cancer cells. Compound C was demonstrated to induce EGR-1 mRNA and protein expression in a time and dose-dependent manner. Confocal imaging showed that compound C-induced EGR-1 protein expression was localized in the nucleus. Compound C was demonstrated to activate extracellular signal-regulated kinase (ERK) phosphorylation. Inhibition of this compound C-induced ERK phosphorylation downregulated the mRNA and protein expression of EGR-1. In addition, removal of compound C-induced reactive oxygen species (ROS) not only decreased ERK phosphorylation, but also inhibited compound C-induced EGR-1 expression. A functional assay showed that knock down of EGR-1 expression in cancer cells decreased the survival rate while also increasing caspase-3 activity and apoptotic marker expression after compound C treatment. However, no difference in autophagy marker light chain 3-II protein expression was observed between compound C-treated control cells and EGR-1-knockdown cells. Thus, it was concluded that that EGR-1 may antagonize compound C-induced apoptosis but not compound C-induced autophagy through the ROS-mediated ERK activation pathway.

Gemcitabine resistance in non‐small cell lung cancer is mediated through activation of the PI3K/AKT/NF‐κB pathway and suppression of ERK signaling by reactive oxygen species

“…death. [9,37] In addition, one of these MAPK proteins, ERK, plays a crucial role in response to oxidative stress and various physiological processes. [38] In the present study, GEM-induced ROS production was significantly lower in GEM-R CL1-0 cells than in the parental CL1-0 cells.…”

“…[ 36 ] ROS can activate the mitogen‐activated protein kinase (MAPK) pathway to regulate cell proliferation, survival, differentiation, and death. [ 9,37 ] In addition, one of these MAPK proteins, ERK, plays a crucial role in response to oxidative stress and various physiological processes. [ 38 ] In the present study, GEM‐induced ROS production was significantly lower in GEM‐R CL1‐0 cells than in the parental CL1‐0 cells.…”

Gastrodin inhibits high glucose‑induced inflammation, oxidative stress and apoptosis in podocytes by activating the AMPK/Nrf2 signaling pathway

“…MPC5 cells were pretreated with different concentrations of gastrodin (0.1, 1, 10 and 100 µM) for 24 h prior to HG addition (30). MPC5 cells were also pretreated with 20 µM Compound C (AMPK inhibitor, also known as dorsomorphin; Tocris Bioscience) for 1 h before HG treatment (31,32) at 37˚C.…”

Comprehensive analysis of differentially expressed genes reveals the promotive effects of UBE2T on colorectal cancer cell proliferation

“…Western blotting. The western blot assay was performed according to a previous report (20). Total protein was extracted from RKO cells using RIPA lysis buffer (Beyotime Institute of Biotechnology).…”