Pemetrexed exerts anticancer effects by inducing G0/G1‑phase cell cycle arrest and activating the NOXA/Mcl‑1 axis in human esophageal squamous cell carcinoma cells

Li,Xinying; Song,Hongxia; Kong,Feng; Guo,Yanxia; Chen,Yuan; Zhang,Lu; Gao,Dongfang; Zhao,Xiaofei; Zhang,Han

doi:10.3892/ol.2018.9753

Pemetrexed exerts anticancer effects by inducing G0/G1‑phase cell cycle arrest and activating the NOXA/Mcl‑1 axis in human esophageal squamous cell carcinoma cells

Authors:
- Xinying Li
- Hongxia Song
- Feng Kong
- Yanxia Guo
- Yuan Chen
- Lu Zhang
- Dongfang Gao
- Xiaofei Zhao
- Han Zhang
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Affiliations: Department of Ophthalmology, Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China, Department of Ozone Treatment, Jinan Infectious Disease Hospital, Jinan, Shandong 250021, P.R. China, Department of Central Research Laboratory, Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
Published online on: November 23, 2018 https://doi.org/10.3892/ol.2018.9753
Pages: 1851-1858

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Abstract

Esophageal squamous cell carcinoma (ESCC) is a dominant histological subtype of esophageal cancer with notably high incidence and mortality rates. Pemetrexed is a clinical antifolate therapeutic agent with anticancer properties. The present study aimed to understand whether pemetrexed is able to exert anticancer effects on ESCC cells, and to determine the underlying molecular mechanism. ESCC cells were treated with pemetrexed and cell survival was assessed with MTT assays. The cell cycle and apoptosis were evaluated using flow cytometry analysis, and proteins were detected using western blotting. It was demonstrated that pemetrexed inhibited cell survival and induced G0/G1 cell cycle arrest and apoptosis in human ESCC cells. Furthermore, the results demonstrated that the phorbol‑12‑myristate‑13‑acetate‑induced protein 1/induced myeloid leukemia cell differentiation protein Mcl‑1 axis is involved in intrinsic apoptosis induced by pemetrexed. The protein expression of endoplasmic reticulum stress markers inositol‑requiring enzyme 1α, binding immunoglobulin protein and CCAAT‑enhancer‑binding protein homologous protein were upregulated following treatment with pemetrexed. These results suggest that pemetrexed may induce an endoplasmic reticulum stress response while activating intrinsic apoptosis. The present study provided important mechanistic insights into potential cancer treatments involving pemetrexed and enhanced the understanding of human ESCC.

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