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CIP2A mediates erlotinib-induced apoptosis in non-small cell lung cancer cells without EGFR mutation.

Publication ,  Journal Article
Wang, C-Y; Chao, T-T; Chang, F-Y; Chen, Y-L; Tsai, Y-T; Lin, H-I; Huang, Y-CT; Shiau, C-W; Yu, C-J; Chen, K-F
Published in: Lung Cancer
August 2014

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors show favorable clinical response in some patients with non-small cell lung cancer (NSCLC) who have no EGFR mutation, indicating alternative mechanisms for their tumoricidal effects. We previously showed erlotinib, a selective EGFR antagonist, inhibited the growth of sensitive hepatocellular carcinoma cells by inhibiting the cancerous inhibitor of protein phosphatase 2A (CIP2A) pathway. The aim of this study was to determine if erlotinib can also inhibit the growth of NSCLC cells by inactivating the CIP2A-dependent signaling pathway. METHODS: Four NSCLC cell lines (H358 H441 H460 and A549) were treated with erlotinib to determine their sensitivity to erlotinib-induced cell death and apoptosis. Expression of CIP2A and the downstream AKT were analyzed. The effects of CIP2A on erlotinib-induced apoptosis were confirmed by overexpression of CIP2A and knockdown of CIP2A gene expression in the sensitive cells and resistant cells, respectively. In vivo efficacy of erlotinib against H358 xenograft tumor was also determined in nude mice. RESULTS: Erlotinib induced significant cell death and apoptosis in H358 and H441 cells, as evidenced by increased caspase 3 activity and cleavage of pro-caspase 9 and PARP, but not in H460 or A549 cells. The apoptotic effect of erlotinib in the sensitive H358 cells was associated with downregulation of CIP2A, increase in PP2A activity and decrease in AKT phosphorylation. Overexpression of CIP2A and AKT protected the sensitive H358 cells from erlotinib-induced apoptosis. Knockdown of CIP2A gene expression by siRNA enhanced the erlotinib-induced apoptotic in the resistant H460 cells that resembled the sensitive H358 cells. Erlotinib also inhibited the growth of H358 tumors in nude mice. CONCLUSIONS: The CIP2A-dependent pathway mediates the tumoricidal effects of erlotinib on NSCLC cells without EGFR mutations in vitro and in vivo. CIP2A may be a novel molecular target against NSCLC for future drug development.

Duke Scholars

Published In

Lung Cancer

DOI

EISSN

1872-8332

Publication Date

August 2014

Volume

85

Issue

2

Start / End Page

152 / 160

Location

Ireland

Related Subject Headings

  • Transcription, Genetic
  • Signal Transduction
  • Quinazolines
  • Proto-Oncogene Proteins c-akt
  • Protein Phosphatase 2
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Mice
  • Membrane Proteins
  • Lung Neoplasms
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Wang, C.-Y., Chao, T.-T., Chang, F.-Y., Chen, Y.-L., Tsai, Y.-T., Lin, H.-I., … Chen, K.-F. (2014). CIP2A mediates erlotinib-induced apoptosis in non-small cell lung cancer cells without EGFR mutation. Lung Cancer, 85(2), 152–160. https://doi.org/10.1016/j.lungcan.2014.05.024
Wang, Cheng-Yi, Ting-Ting Chao, Fang-Yu Chang, Yen-Lin Chen, Yi-Ting Tsai, Hen-I Lin, Yuh-Chin T. Huang, Chung-Wai Shiau, Chong-Jen Yu, and Kuen-Feng Chen. “CIP2A mediates erlotinib-induced apoptosis in non-small cell lung cancer cells without EGFR mutation.Lung Cancer 85, no. 2 (August 2014): 152–60. https://doi.org/10.1016/j.lungcan.2014.05.024.
Wang C-Y, Chao T-T, Chang F-Y, Chen Y-L, Tsai Y-T, Lin H-I, et al. CIP2A mediates erlotinib-induced apoptosis in non-small cell lung cancer cells without EGFR mutation. Lung Cancer. 2014 Aug;85(2):152–60.
Wang, Cheng-Yi, et al. “CIP2A mediates erlotinib-induced apoptosis in non-small cell lung cancer cells without EGFR mutation.Lung Cancer, vol. 85, no. 2, Aug. 2014, pp. 152–60. Pubmed, doi:10.1016/j.lungcan.2014.05.024.
Wang C-Y, Chao T-T, Chang F-Y, Chen Y-L, Tsai Y-T, Lin H-I, Huang Y-CT, Shiau C-W, Yu C-J, Chen K-F. CIP2A mediates erlotinib-induced apoptosis in non-small cell lung cancer cells without EGFR mutation. Lung Cancer. 2014 Aug;85(2):152–160.
Journal cover image

Published In

Lung Cancer

DOI

EISSN

1872-8332

Publication Date

August 2014

Volume

85

Issue

2

Start / End Page

152 / 160

Location

Ireland

Related Subject Headings

  • Transcription, Genetic
  • Signal Transduction
  • Quinazolines
  • Proto-Oncogene Proteins c-akt
  • Protein Phosphatase 2
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Mice
  • Membrane Proteins
  • Lung Neoplasms