Gallic acid inhibition of Src-Stat3 signaling overcomes acquired resistance to EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer

Ai N.H. Phan, Tuyen N.M. Hua, Min kyu Kim, Vu T.A. Vo, Jong Whan Choi, Hyun Won Kim, Jin Kyung Rho, Ki Woo Kim, Yangsik Jeong

Research output: Contribution to journalArticle

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Abstract

Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have clinically benefited to lung cancer patients harboring a subset of activating EGFR mutations. However, even with the remarkable therapeutic response at the initial TKI treatment, most lung cancer patients eventually have relapsed aggressive tumors due to acquired resistance to the TKIs. Here, we report that 3, 4, 5-trihydroxybenzoic acid or gallic acid (GA), a natural polyphenolic compound, shows anti-tumorigenic effects in TKI-resistant non-small cell lung cancer (NSCLC). Using both in vitro growth assay and in vivo xenograft animal model, we demonstrated tumor suppressive effect of GA was more selective for the TKI-resistant cancer compared to the TKI-sensitive one. Mechanistically, GA treatment inhibited Src-Stat3-mediated signaling and decreased the expression of Stat3-regulated tumor promoting genes, subsequently inducing apoptosis and cell cycle arrest in the TKI-resistant lung cancer but not in the TKI-sensitive one. Consistent with the in vitro results, in vivo xenograft experiments showed the TKI-resistant tumor-selective growth inhibition and suppression of Src-Stat3-dependent signaling in the GA-treated tumors isolated from the xenograft model. This finding identified an importance of Src-Stat3 signaling cascade in GA-mediated tumor-suppression activity and, more importantly, provides a novel therapeutic insight of GA for advanced TKI-resistant lung cancer.

Original languageEnglish
Pages (from-to)54702-54713
Number of pages12
JournalOncotarget
Volume7
Issue number34
DOIs
Publication statusPublished - 2016 Jan 1

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Gallic Acid
Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Lung Neoplasms
Neoplasms
Heterografts
Therapeutics
Growth
Cell Cycle Checkpoints
Animal Models
Apoptosis

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Phan, Ai N.H. ; Hua, Tuyen N.M. ; Kim, Min kyu ; Vo, Vu T.A. ; Choi, Jong Whan ; Kim, Hyun Won ; Rho, Jin Kyung ; Kim, Ki Woo ; Jeong, Yangsik. / Gallic acid inhibition of Src-Stat3 signaling overcomes acquired resistance to EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer. In: Oncotarget. 2016 ; Vol. 7, No. 34. pp. 54702-54713.
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abstract = "Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have clinically benefited to lung cancer patients harboring a subset of activating EGFR mutations. However, even with the remarkable therapeutic response at the initial TKI treatment, most lung cancer patients eventually have relapsed aggressive tumors due to acquired resistance to the TKIs. Here, we report that 3, 4, 5-trihydroxybenzoic acid or gallic acid (GA), a natural polyphenolic compound, shows anti-tumorigenic effects in TKI-resistant non-small cell lung cancer (NSCLC). Using both in vitro growth assay and in vivo xenograft animal model, we demonstrated tumor suppressive effect of GA was more selective for the TKI-resistant cancer compared to the TKI-sensitive one. Mechanistically, GA treatment inhibited Src-Stat3-mediated signaling and decreased the expression of Stat3-regulated tumor promoting genes, subsequently inducing apoptosis and cell cycle arrest in the TKI-resistant lung cancer but not in the TKI-sensitive one. Consistent with the in vitro results, in vivo xenograft experiments showed the TKI-resistant tumor-selective growth inhibition and suppression of Src-Stat3-dependent signaling in the GA-treated tumors isolated from the xenograft model. This finding identified an importance of Src-Stat3 signaling cascade in GA-mediated tumor-suppression activity and, more importantly, provides a novel therapeutic insight of GA for advanced TKI-resistant lung cancer.",
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Gallic acid inhibition of Src-Stat3 signaling overcomes acquired resistance to EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer. / Phan, Ai N.H.; Hua, Tuyen N.M.; Kim, Min kyu; Vo, Vu T.A.; Choi, Jong Whan; Kim, Hyun Won; Rho, Jin Kyung; Kim, Ki Woo; Jeong, Yangsik.

In: Oncotarget, Vol. 7, No. 34, 01.01.2016, p. 54702-54713.

Research output: Contribution to journalArticle

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AU - Phan, Ai N.H.

AU - Hua, Tuyen N.M.

AU - Kim, Min kyu

AU - Vo, Vu T.A.

AU - Choi, Jong Whan

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AU - Kim, Ki Woo

AU - Jeong, Yangsik

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