Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo

• DOI: 10.3389/fonc.2022.936145
• Publication Date: 2022-07-05T20:02:06Z
• Authors: Reetobrata Basu; Yanrong Qian; Samuel Mathes; Joseph Terry; Nathan Arnett; Trent Riddell; Austin Stevens; Kevin Funk; Stephen Bell; Zac Bokal; Courtney Batten; Cole Smith; Isaac Mendez-Gibson; Silvana Duran-Ortiz; Grace Lach; Patricia Alexandr...; Prateek Kulkarni; Emily Davis; Elizabeth Teaford; Darlene E. Berryman; Edward O. List; Sebastian Neggers; John J. Kopchick
• Keywords: growth hormone (GH); 0301 basic medicine; 03 medical and health sciences; GHA; ABC transporters; Oncology; melanoma; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; HCC; growth hormone receptor antagonist (GHRA); RC254-282; 3. Good health

Knockdown of GH receptor (GHR) in melanoma cells vitro downregulates ATP-binding cassette-containing (ABC) transporters and sensitizes them to anti-cancer drug treatments. Here we aimed determine whether a GHR antagonist (GHRA) could control cancer growth by sensitizing tumors therapy through downregulation ABC vivo. We intradermally inoculated Fluc-B16-F10 mouse into GHA mice, transgenic for (GHRA), observed marked reduction tumor size, mass tumoral signaling. Moreover, constitutive GHRA production the mice significantly improved response cisplatin treatment suppressing expression multiple drug. confirmed that presence not mere absence is essential this chemo-sensitizing effect using allografts knockout (GHKO) where was reduced relative GH-sufficient controls but did sensitize cisplatin. extended our investigation hepatocellular carcinoma (HCC) human HCC syngeneic model with Hepa1-6 mice. Gene analyses drug-efflux assays confirm blocking suppresses levels improves efficacy sorafenib towards almost complete clearance. Human patient data show RNA correlate transporter expression. Collectively, results validate vivo combination currently available therapies can be effective attacking resistance.