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ANXA1 silencing increases the sensitivity of cancer cells to low-concentration arsenic trioxide treatment by inhibiting ERK MAPK activation

Abstract

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.

Methods

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.

Results

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.

Conclusions

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

DOI:10.5301/tj.5000315

Authors

Xueyan Zhang, Xiaodong Li, Xiaolin Li, Lei Zheng, Lei Lei

Article History

Disclosures

Financial support: Supported by the Science and Technology Program of Education, Department of Heilongjiang Province, China (No. 12511288).
Conflict of interest: None.

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Authors

Affiliations

  • Department of Gastroenterology, The Second Hospital Affiliated to Harbin Medical University, Harbin - China
  • Department of Histology and Embryology, Harbin Medical University, Harbin - China

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