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

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 Alexandra Mora-Criollo, Prateek Kulkarni, Emily Davis, Elizabeth Teaford, Darlene E. BerrymanEdward O. List, Sebastian Neggers, John J. Kopchick*

*Corresponding author for this work

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Abstract

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

Original languageEnglish
Article number936145
JournalFrontiers in Oncology
Volume12
DOIs
Publication statusPublished - 5 Jul 2022
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported, in part, by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll to JK, National Institutes of Health (NIH)-R01AG059779 to JK; Ohio University Research Council, Baker Fund, and PACE Funds from Ohio University to YQ; the Provost Undergraduate Research Funds and the John J. Kopchick Molecular Cell Biology/Translational Biomedical Sciences Undergraduate Student Support Funds to NA and JT; Student Enhancement Award and Dr. Sig Maier Undergraduate Research Fund to JT; the AMVETS, the Edison Biotechnology and Diabetes Institutes at Ohio University.

Publisher Copyright:
Copyright © 2022 Basu, Qian, Mathes, Terry, Arnett, Riddell, Stevens, Funk, Bell, Bokal, Batten, Smith, Mendez-Gibson, Duran-Ortiz, Lach, Mora-Criollo, Kulkarni, Davis, Teaford, Berryman, List, Neggers and Kopchick.

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