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

Chuang,Kai-Cheng; Chen,Fan-Wen; Tsai,Meng-Hsiun; Shieh,Jeng-Jer

doi:10.3892/ol.2021.12565

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

Authors:
- Kai-Cheng Chuang
- Fan-Wen Chen
- Meng-Hsiun Tsai
- Jeng-Jer Shieh
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Affiliations: Institute of Biomedical Sciences, National Chung Hsing University, Taichung 402, Taiwan, R.O.C., Department of Management Information System, National Chung Hsing University, Taichung 402, Taiwan, R.O.C.
Published online on: February 19, 2021 https://doi.org/10.3892/ol.2021.12565
Article Number: 304

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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.

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