Effects of sorafenib and an adenylyl cyclase activator on <i>in vitro</i> growth of well-differentiated thyroid cancer cells

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Author(s)

    • Sawa Aya
    • Department of Pathology, School of Medicine, Kyorin University, Mitaka-shi, 181-8611, Japan|Department of Breast and Endocrine Surgery, University of Tsukuba Hospital, Tsukuba 305-8576, Japan
    • Chiba Tomohiro
    • Department of Pathology, School of Medicine, Kyorin University, Mitaka-shi, 181-8611, Japan
    • Ishii Jun
    • Department of Pathology, School of Medicine, Kyorin University, Mitaka-shi, 181-8611, Japan
    • Yamamoto Hiroyuki
    • Department of Pathology, School of Medicine, Kyorin University, Mitaka-shi, 181-8611, Japan|Division of Nephrology and Endocrinology, The University of Tokyo, Tokyo 113-8655, Japan
    • Hara Hisato
    • Department of Breast and Endocrine Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
    • Kamma Hiroshi
    • Department of Pathology, School of Medicine, Kyorin University, Mitaka-shi, 181-8611, Japan

Abstract

Well-differentiated thyroid carcinomas have driver mutations involving growth factor receptor-tyrosine kinases (RTKs) or their intracellular signaling pathway, that is, the mitogen-activated protein kinase (MAPK) pathway. Sorafenib is a multikinase inhibitor of RTKs and the MAPK pathway and has recently been used for the treatment of unresectable well-differentiated thyroid carcinoma. In normal thyroid follicular cells, stimulation of the thyroid-stimulating hormone (TSH) receptor activates the cyclic adenosine monophosphate (cAMP) pathway and promotes cell growth as well as hormonal secretion. However, an adenylyl cyclase (AC) activator, forskolin, has been reported to suppress the growth of thyroid carcinoma cells. To clarify the roles of the MAPK and cAMP pathways in proliferation of well-differentiated thyroid carcinoma cells, we compared the effects of sorafenib and forskolin in <i>in vitro</i> models. Sorafenib inhibited constitutive activation of the MAPK pathway, cyclin-dependent kinase 4 (CDK4), and phosphorylated retinoblastoma protein (RB) in 3 well-differentiated carcinoma cell lines, but it did not show sufficiently effective suppression of cell growth. Forskolin significantly suppressed the growth of all 3 cell lines and also activated the cAMP pathway and inhibited expression of cyclin D1. Our results suggest that activation of the cAMP pathway could be more potent than activation of the MAPK pathway in suppressing proliferation of well-differentiated thyroid cancer cells. We postulate that the AC activator suppresses growth of thyroid carcinoma cells through undetermined mechanisms.

Journal

  • Endocrine Journal

    Endocrine Journal 64(11), 1115-1123, 2017

    The Japan Endocrine Society

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