ANXA1 silencing increases the sensitivity of cancer cells to low-concentration arsenic trioxide treatment by inhibiting ERK MAPK activation
Aims and background
Arsenic trioxide (ATO), an antitumor agent, is widely used for treating acute promyelocytic leukemia (APL), in which it induces apoptosis. In most solid tumors, ATO disturbs the cell cycle instead of inducing apoptosis. We aimed to determine the exact mechanism underlying the different response of APL to ATO compared with the response of solid tumors.
A proteomics-based screening was used to identify the ATO-associated proteins in the human esophageal squamous cell carcinoma cell line, Eca109. The expression levels of Annexin A1 (ANXA1) in 4 different types of cancer cells were determined by quantitative reverse transcription polymerase chain reaction and Western blotting. Human esophageal squamous cell carcinoma cell line Eca109 and pancreatic carcinoma cell line BxPC3 cells were transfected with siRNAs targeting ANXA1 and scrambled control siRNA. Cell proliferation was evaluated by methyl thiazolyl tetrazolium assay.
After verification of the mRNA and protein levels in 4 cancer cell lines, ANXA1 and lamin A/B were validated to have increased expression levels after low-concentration ATO treatment. Lower concentrations of ATO, which has no effect on proliferation of cancer cells, induced apoptosis after ANXA1 silencing. Furthermore, overexpression of ANXA1 induced by ATO resulted in activation of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases (MAPKs), rendering cancer cells resistant to the agent. In addition, PD98059, a specific ERK inhibitor, increased the sensitivity of cancer cells to a lower concentration of ATO treatment.
Taken together, these data indicate that overexpression of ANXA1 induced by low-concentration ATO makes cancer cells more resistant to the agent via activated ERK MAPKs. Specific silencing of ANXA1 increased the sensitivity of cancer cells to ATO treatment.
Tumori 2015; 101(4): 360 - 367
Article Type: ORIGINAL RESEARCH ARTICLE
Xueyan Zhang, Xiaodong Li, Xiaolin Li, Lei Zheng, Lei Lei
• Accepted on 14/01/2015
• Available online on 13/05/2015
• Published in print on 24/07/2015
Financial support: Supported by the Science and Technology Program of Education, Department of Heilongjiang Province, China (No. 12511288).
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