title: Growth Hormone Receptor Knockdown Sensitizes Human Melanoma Cells to Chemotherapy by Attenuating Expression of ABC Drug Efflux Pumps.
abstract: Melanoma remains one of the most therapy-resistant forms of human cancer despite recent introductions of highly efficacious targeted therapies. The intrinsic therapy resistance of human melanoma is largely due to abundant expression of a repertoire of xenobiotic efflux pumps of the ATP-binding cassette (ABC) transporter family. Here, we report that GH action is a key mediator of chemotherapeutic resistance in human melanoma cells. We investigated multiple ABC efflux pumps (ABCB1, ABCB5, ABCB8, ABCC1, ABCC2, ABCG1, and ABCG2) reportedly associated with melanoma drug resistance in different human melanoma cells and tested the efficacy of five different anti-cancer compounds (cisplatin, doxorubicin, oridonin, paclitaxel, vemurafenib) with decreased GH action. We found that GH treatment of human melanoma cells upregulates expression of multiple ABC transporters and increases the EC50 of melanoma drug vemurafenib. Also, vemurafenib-resistant melanoma cells had upregulated levels of GH receptor (GHR) expression as well as ABC efflux pumps. GHR knockdown (KD) using siRNA in human melanoma cells treated with sub-EC50 doses of anti-tumor compounds resulted in significantly increased drug retention, decreased cell proliferation and increased drug efficacy, compared to mock-transfected controls. Our set of findings identify an unknown mechanism of GH regulation in mediating melanoma drug resistance and validates GHR as a unique therapeutic target for sensitizing highly therapy-resistant human melanoma cells to lower doses of anti-cancer drugs.
authors.affiliation: Edison Biotechnology Institute, Konneker Research Laboratory 206, Ohio University, Athens, OH, 45701, USA.|Molecular and Cell Biology Program, Ohio University, Athens, OH, USA.
authors.forename: Reetobrata
authors.identifier: http://orcid.org/0000-0001-8415-1356
authors.initials: R
authors.lastname: Basu
authors.affiliation: Edison Biotechnology Institute, Konneker Research Laboratory 206, Ohio University, Athens, OH, 45701, USA.|Department of Biological Sciences, Ohio University, Athens, OH, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Baumgaertel
authors.affiliation: Edison Biotechnology Institute, Konneker Research Laboratory 206, Ohio University, Athens, OH, 45701, USA.|Molecular and Cell Biology Program, Ohio University, Athens, OH, USA.
authors.forename: Shiyong
authors.initials: S
authors.lastname: Wu
authors.affiliation: Edison Biotechnology Institute, Konneker Research Laboratory 206, Ohio University, Athens, OH, 45701, USA. kopchick@ohio.edu.|Molecular and Cell Biology Program, Ohio University, Athens, OH, USA. kopchick@ohio.edu.|Heritage College of Osteopathic Medicine, Athens, OH, USA. kopchick@ohio.edu.
authors.forename: John J
authors.initials: JJ
authors.lastname: Kopchick
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000089762:Multidrug Resistance-Associated Protein 2; D017239:Paclitaxel / Q000008:administration & dosage; D011986:Receptors, Somatotropin / Q000037:antagonists & inhibitors / Q000235:genetics*; D013449:Sulfonamides / Q000008:administration & dosage; D000077484:Vemurafenib
chemical_list: C000715087:ABCC2 protein, human; D000970:Antineoplastic Agents; D007211:Indoles; D000089762:Multidrug Resistance-Associated Protein 2; D011986:Receptors, Somatotropin; D013449:Sulfonamides; D000077484:Vemurafenib; D004317:Doxorubicin; D017239:Paclitaxel