Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10753531 | Biochemical and Biophysical Research Communications | 2015 | 6 Pages |
Abstract
Identification of efficient chemo-therapeutic/chemo-preventive agents for treatment of hepatocellular carcinoma (HCC) is important. In this study, we examined the activity of pemetrexed, an anti-folate chemotherapy drug, against HepG2 human HCC cells. Pemetrexed treatment in vitro exerted weak but significant cytotoxic activity against HepG2 cells. When analyzing the possible pemetrexed-resistance factors, we indentified that pemetrexed treatment in HepG2 cells induced cyto-protective autophagy activation, evidenced by GFP-light chain 3B (LC3B) puncta formation, p62 downregulation and Beclin-1/LC3B-II upregulation. Correspondingly, autophagy inhibitors, including bafliomycin A1, 3-methyladenine and chloroquine, enhanced pemetrexed-induced cytotoxicity against HepG2 cells. Further, RNAi-mediated knockdown of Beclin-1 in HepG2 cells also increased pemetrexed sensitivity. Pemetrexed activated MEK (mitogen-activated protein kinase/ERK kinase)/ERK (extracellular-signal-regulated kinase) signaling in HepG2 cells, which was required for autophagy induction. Pharmacological inhibition of MEK/ERK activation attenuated pemetrexed-induced autophagy, enhanced HepG2 cell death and apoptosis. In summary, pemetrexed activates MEK/ERK-dependent cyto-protective autophagy, and inhibition of this pathway potentiates pemetrexed's activity in HepG2 cells.
Keywords
LC-3mitogen-activated protein kinase/ERK kinase3-MAGFPERK3-methyladenineHCCAutophagyBaf A1bafilomycin A1Enzyme-linked immunosorbent assayELISAChemo-sensitizationlight chain 3MEKGreen fluorescence proteinPemetrexedHepatocellular carcinoma (HCC)Hepatocellular carcinomaChloroquineextracellular-signal-regulated kinase
Related Topics
Life Sciences
Biochemistry, Genetics and Molecular Biology
Biochemistry
Authors
Tong Yongxi, Huang Haijun, Pan Hongying,