Growth Hormone Upregulates Mediators of Melanoma Drug Efflux and Epithelial-to-Mesenchymal Transition In Vitro and In Vivo

Yanrong Qian; Reetobrata Basu; Samuel C Mathes; Nathan A Arnett; Silvana Duran-Ortiz; Kevin R Funk; Alison L Brittain; Prateek Kulkarni; Joseph C Terry; Emily Davis; Jordyn T Singerman; Brooke E Henry; Edward O List; Darlene E Berryman; John J Kopchick

doi:10.3390/cancers12123640

Growth Hormone Upregulates Mediators of Melanoma Drug Efflux and Epithelial-to-Mesenchymal Transition In Vitro and In Vivo

Cancers (Basel). 2020 Dec 4;12(12):3640. doi: 10.3390/cancers12123640.

Authors

Yanrong Qian¹, Reetobrata Basu¹, Samuel C Mathes^{1

2}, Nathan A Arnett^{1

3}, Silvana Duran-Ortiz^{1

2

4}, Kevin R Funk^{1

2

4}, Alison L Brittain^{1

4

5}, Prateek Kulkarni^{1

2

4}, Joseph C Terry^{1

2}, Emily Davis^{1

2

4}, Jordyn T Singerman^{1

2}, Brooke E Henry¹, Edward O List¹, Darlene E Berryman^{1

5}, John J Kopchick^{1

4

5}

Affiliations

¹ Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.
² Department of Biological Sciences, Ohio University, Athens, OH 45701, USA.
³ Russ College of Engineering, Ohio University, Athens, OH 45701, USA.
⁴ Molecular Cellular Biology Program, Ohio University, Athens, OH 45701, USA.
⁵ Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA.

Abstract

Growth hormone (GH) and the GH receptor (GHR) are expressed in a wide range of malignant tumors including melanoma. However, the effect of GH/insulin-like growth factor (IGF) on melanoma in vivo has not yet been elucidated. Here we assessed the physical and molecular effects of GH on mouse melanoma B16-F10 and human melanoma SK-MEL-30 cells in vitro. We then corroborated these observations with syngeneic B16-F10 tumors in two mouse lines with different levels of GH/IGF: bovine GH transgenic mice (bGH; high GH, high IGF-1) and GHR gene-disrupted or knockout mice (GHRKO; high GH, low IGF-1). In vitro, GH treatment enhanced mouse and human melanoma cell growth, drug retention and cell invasion. While the in vivo tumor size was unaffected in both bGH and GHRKO mouse lines, multiple drug-efflux pumps were up regulated. This intrinsic capacity of therapy resistance appears to be GH dependent. Additionally, epithelial-to-mesenchymal transition (EMT) gene transcription markers were significantly upregulated in vivo supporting our current and recent in vitro observations. These syngeneic mouse melanoma models of differential GH/IGF action can be valuable tools in screening for therapeutic options where lowering GH/IGF-1 action is important.

Keywords: epithelial-to-mesenchymal transition; growth hormone; growth hormone receptor; insulin-like growth factor-1; melanoma; multidrug efflux pumps.

Abstract

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