Antitumor impact of p14ARF on gefitinib-resistant non-small cell lung cancers

Ken Saito, Nagio Takigawa, Naoko Ohtani, Hidekazu Iioka, Yuki Tomita, Ryuzo Ueda, Junya Fukuoka, Kazuhiko Kuwahara, Eiki Ichihara, Katsuyuki Kiura, Eisaku Kondo

Research output: Contribution to journalArticle

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Abstract

Activation of the epidermal growth factor receptor (EGFR) has been observed in many malignant tumors and its constitutive signal transduction facilitates the proliferation of tumors. EGFR-tyrosine kinase inhibitors, such as gefitinib, are widely used as a molecular-targeting agent for the inactivation of EGFR signaling and show considerable therapeutic effect in non-small cell lung cancers harboring activating EGFR mutations. However, prolonged treatment inevitably produces tumors with additional gefitinibresistant mutations in EGFR, which is a critical issue for current therapeutics.We aimed to characterize the distinct molecular response to gefitinib between the drug-resistant and drug-sensitive lung adenocarcinoma cells in order to learn about therapeutics based on the molecular information. From the quantitative PCR analysis, we found a specific increase in p14ARF expression in gefitinib-sensitive lung adenocarcinoma clones, which was absent in gefitinib-resistant clones. Moreover, mitochondria-targeted p14ARF triggered themost augmented apoptosis in both clones. We identified the amino acid residues spanning from 38 to 65 as a functional core of mitochondrial p14ARF (p14 38-65 a.a.), which reduced the mitochondrial membrane potential and caused caspase-9 activation. The synthesized peptide covering the p14 38-65 a.a. induced growth suppression of the gefitinib-resistant clones without affecting nonneoplastic cells. Notably, transduction of the minimized dose of the p14 38-65 peptide restored the response to gefitinib like that in the sensitive clones. These findings suggest that the region of p14ARF 38-65 a.a. is critical in the pharmacologic action of gefitinib against EGFR-mutated lung adenocarcinoma cells and has potential utility in the therapeutics of gefitinib-resistant cancers. Mol Cancer Ther; 12(8); 1616-28.

Original languageEnglish
Pages (from-to)1616-1628
Number of pages13
JournalMolecular Cancer Therapeutics
Volume12
Issue number8
DOIs
Publication statusPublished - Aug 2013

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Tumor Suppressor Protein p14ARF
Non-Small Cell Lung Carcinoma
Epidermal Growth Factor Receptor
Clone Cells
Neoplasms
Pharmacologic Actions
Peptides
Mutation
gefitinib
Caspase 9
Mitochondrial Membrane Potential
Therapeutic Uses
Pharmaceutical Preparations
Protein-Tyrosine Kinases
Signal Transduction
Mitochondria
Therapeutics
Apoptosis
Amino Acids
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Medicine(all)

Cite this

Saito, K., Takigawa, N., Ohtani, N., Iioka, H., Tomita, Y., Ueda, R., ... Kondo, E. (2013). Antitumor impact of p14ARF on gefitinib-resistant non-small cell lung cancers. Molecular Cancer Therapeutics, 12(8), 1616-1628. https://doi.org/10.1158/1535-7163.MCT-12-1239

Antitumor impact of p14ARF on gefitinib-resistant non-small cell lung cancers. / Saito, Ken; Takigawa, Nagio; Ohtani, Naoko; Iioka, Hidekazu; Tomita, Yuki; Ueda, Ryuzo; Fukuoka, Junya; Kuwahara, Kazuhiko; Ichihara, Eiki; Kiura, Katsuyuki; Kondo, Eisaku.

In: Molecular Cancer Therapeutics, Vol. 12, No. 8, 08.2013, p. 1616-1628.

Research output: Contribution to journalArticle

Saito, K, Takigawa, N, Ohtani, N, Iioka, H, Tomita, Y, Ueda, R, Fukuoka, J, Kuwahara, K, Ichihara, E, Kiura, K & Kondo, E 2013, 'Antitumor impact of p14ARF on gefitinib-resistant non-small cell lung cancers', Molecular Cancer Therapeutics, vol. 12, no. 8, pp. 1616-1628. https://doi.org/10.1158/1535-7163.MCT-12-1239
Saito, Ken ; Takigawa, Nagio ; Ohtani, Naoko ; Iioka, Hidekazu ; Tomita, Yuki ; Ueda, Ryuzo ; Fukuoka, Junya ; Kuwahara, Kazuhiko ; Ichihara, Eiki ; Kiura, Katsuyuki ; Kondo, Eisaku. / Antitumor impact of p14ARF on gefitinib-resistant non-small cell lung cancers. In: Molecular Cancer Therapeutics. 2013 ; Vol. 12, No. 8. pp. 1616-1628.
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