Research Papers:

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 and Yangsik Jeong _

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Oncotarget. 2016; 7:54702-54713. https://doi.org/10.18632/oncotarget.10581

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Ai N.H. Phan1,2, Tuyen N.M. Hua1,2, Min-Kyu Kim1,2, Vu T.A. Vo1,2, Jong-Whan Choi1, Hyun-Won Kim1, Jin Kyung Rho3, Ki Woo Kim2,4, Yangsik Jeong1,2

1Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea

2Department of Global Medical Science, Institute of Lifestyle Medicine, Nuclear Receptor Research Consortium, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea

3Department of Convergence Medicine, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Republic of Korea

4Department of Pharmacology, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea

Correspondence to:

Yangsik Jeong, email: [email protected]

Keywords: gallic acid, Src, Stat3, EGFR-TKI resistance, lung cancer

Received: April 27, 2016     Accepted: June 30, 2016     Published: July 13, 2016


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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