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CI-988 Inhibits EGFR Transactivation and Proliferation Caused by Addition of CCK/Gastrin to Lung Cancer Cells

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Abstract

Cholecystokinin (CCK) receptors are G-protein coupled receptors (GPCR) which are present on lung cancer cells. CCK-8 stimulates the proliferation of lung cancer cells, whereas the CCK2R receptor antagonist CI-988 inhibits proliferation. GPCR for some gastrointestinal hormones/neurotransmitters mediate lung cancer growth by causing epidermal growth factor receptor (EGFR) transactivation. Here, the role of CCK/gastrin and CI-988 on EGFR transactivation and lung cancer proliferation was investigated. Addition of CCK-8 or gastrin-17 (100 nM) to NCI-H727 human lung cancer cells increased EGFR Tyr1068 phosphorylation after 2 min. The ability of CCK-8 to cause EGFR tyrosine phosphorylation was blocked by CI-988, gefitinib (EGFR tyrosine kinase inhibitor), PP2 (Src inhibitor), GM6001 (matrix metalloprotease inhibitor), and tiron (superoxide scavenger). CCK-8 nonsulfated and gastrin-17 caused EGFR transactivation and bound with high affinity to NCI-H727 cells, suggesting that the CCK2R is present. CI-988 inhibited the ability of CCK-8 to cause ERK phosphorylation and elevate cytosolic Ca2+. CI-988 or gefitinib inhibited the basal growth of NCI-H727 cells or that stimulated by CCK-8. The results indicate that CCK/gastrin may increase lung cancer proliferation in an EGFR-dependent manner.

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Acknowledgments

The authors thank Dr. J. Hughes for the CI-988 and Dr. D. Chan for the helpful discussions. This research is supported by the NIH intramural programs of NIDDK and NCI.

Conflict of Interest

The authors state that there are no conflicts of interest to disclose.

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Authors and Affiliations

  1. Department of Health and Human Services, National Cancer Institute, Center for Cancer Research, Office of the Director, 9609 Medical Center Drive, Room 2 W-130, Bethesda, MD, 20892, USA

    Terry W. Moody

  2. National Institute of Diabetes, Digestive and Kidney Disease, Digestive Diseases Branch, National Institutes of Health, Bethesda, MD, 20892, USA

    Bernardo Nuche-Berenguer, Paola Moreno & Robert T. Jensen

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  1. Terry W. Moody
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  2. Bernardo Nuche-Berenguer
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  3. Paola Moreno
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  4. Robert T. Jensen
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Correspondence to Terry W. Moody.

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Moody, T.W., Nuche-Berenguer, B., Moreno, P. et al. CI-988 Inhibits EGFR Transactivation and Proliferation Caused by Addition of CCK/Gastrin to Lung Cancer Cells. J Mol Neurosci 56, 663–672 (2015). https://doi.org/10.1007/s12031-015-0533-6

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  • DOI: https://doi.org/10.1007/s12031-015-0533-6

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