Co-targeting PI3K/Akt and MAPK/ERK pathways leads to an enhanced antitumor effect on human hypopharyngeal squamous cell carcinoma
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The present study aims to determine whether co-targeting PI3K/Akt and MAPK/ERK pathways in human hypopharyngeal squamous cell carcinoma (HSCC) is a potential anticancer strategy.
We retrospectively analyzed the clinical data of HSCC patients, and the phosphorylation status of Akt and Erk in HSCC and tumor adjacent tissues was evaluated by immunohistochemistry. MTT and colony formation assay were performed to determine the anti-proliferative effect of PI3K/mTOR inhibitor GDC-0980 and MEK inhibitor Refametinib on HSCC cell line Fadu. Wound-healing and Transwell migration assay were used to analyze the anti-migrative capability of the two drugs. The involved anti-tumor mechanism was explored by flow cytometry, qRT-PCR and western blot. The combinational anticancer effect of GDC-0980 and Refametinib was evaluated according to Chou and Talalay’s method.
The levels of p-Akt and p-Erk were increased significantly with the progression of clinical stage of HSCC, suggesting PI3K/Akt and MAPK/ERK pathways might be associated with HSCC occurrence and progression. Furthermore, both GDC-0980 and Refametinib showed obvious antitumor effects on FaDu cells. Treatment by the two drugs arrested FaDu cell cycle progression in G1 phase, with reduction of cyclin D1 and p-Rb, in contrast to enhancement of p27. GDC-0980 inhibited FaDu cell migration and reduced metastasis related proteins including p-PKCζ, p-Integrin β1 and uPA. Combination use of GDC-0980 and Refametinib exhibited strong synergistic anti-tumor effect.
Dual inhibition of PI3K/Akt and MAPK/ERK pathway by GDC-0980 and Refametinib might be a promising treatment strategy for HSCC patients.
KeywordsHypopharyngeal squamous cell carcinoma PI3K/Akt MAPK/ERK Co-targeting G1 phase arrest Combination treatment
The work was supported by grant from National Natural Science Foundation of China (81673464, 81373441), the Grant for Major Project of Tianjin for New Drug Development (17ZXXYSY00050), and the Grant from Natural Science Foundation of Tianjin-Science and Technology (15JCYBJC27500).
XP, YL and SZ performed the experiments. XP, HL and WJ analyzed the data. ZZ, YQ and MJ prepared the figures. YL, XP and RW wrote the main manuscript. DK revised the manuscript. PL, RW and DK designed the experiments. All authors reviewed the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that there are no conflicts of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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