Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo
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 throu...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.936145/full |
| _version_ | 1818533483805409280 |
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| author | Reetobrata Basu Yanrong Qian Samuel Mathes Joseph Terry Joseph Terry Nathan Arnett Nathan Arnett Trent Riddell Trent Riddell Austin Stevens Austin Stevens Kevin Funk Kevin Funk Kevin Funk Stephen Bell Stephen Bell Zac Bokal Courtney Batten Cole Smith Isaac Mendez-Gibson Silvana Duran-Ortiz Grace Lach Grace Lach Patricia Alexandra Mora-Criollo Prateek Kulkarni Prateek Kulkarni Prateek Kulkarni Emily Davis Emily Davis Emily Davis Elizabeth Teaford Darlene E. Berryman Darlene E. Berryman Edward O. List Sebastian Neggers John J. Kopchick John J. Kopchick John J. Kopchick John J. Kopchick |
| author_facet | Reetobrata Basu Yanrong Qian Samuel Mathes Joseph Terry Joseph Terry Nathan Arnett Nathan Arnett Trent Riddell Trent Riddell Austin Stevens Austin Stevens Kevin Funk Kevin Funk Kevin Funk Stephen Bell Stephen Bell Zac Bokal Courtney Batten Cole Smith Isaac Mendez-Gibson Silvana Duran-Ortiz Grace Lach Grace Lach Patricia Alexandra Mora-Criollo Prateek Kulkarni Prateek Kulkarni Prateek Kulkarni Emily Davis Emily Davis Emily Davis Elizabeth Teaford Darlene E. Berryman Darlene E. Berryman Edward O. List Sebastian Neggers John J. Kopchick John J. Kopchick John J. Kopchick John J. Kopchick |
| author_sort | Reetobrata Basu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T17:59:18Z |
| format | Article |
| id | doaj.art-d2ffbe802ebd4cbd9ac35e71d0449a98 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-11T17:59:18Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-d2ffbe802ebd4cbd9ac35e71d0449a982022-12-22T00:55:57ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-07-011210.3389/fonc.2022.936145936145Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivoReetobrata Basu0Yanrong Qian1Samuel Mathes2Joseph Terry3Joseph Terry4Nathan Arnett5Nathan Arnett6Trent Riddell7Trent Riddell8Austin Stevens9Austin Stevens10Kevin Funk11Kevin Funk12Kevin Funk13Stephen Bell14Stephen Bell15Zac Bokal16Courtney Batten17Cole Smith18Isaac Mendez-Gibson19Silvana Duran-Ortiz20Grace Lach21Grace Lach22Patricia Alexandra Mora-Criollo23Prateek Kulkarni24Prateek Kulkarni25Prateek Kulkarni26Emily Davis27Emily Davis28Emily Davis29Elizabeth Teaford30Darlene E. Berryman31Darlene E. Berryman32Edward O. List33Sebastian Neggers34John J. Kopchick35John J. Kopchick36John J. Kopchick37John J. Kopchick38Edison Biotechnology Institute, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesDepartment of Biological Sciences, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesRuss College of Engineering, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesDepartment of Biological Sciences, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesDepartment of Biological Sciences, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesDepartment of Biological Sciences, Ohio University, Athens, OH, United StatesMolecular Cellular Biology Program, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesDepartment of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesDepartment of Biological Sciences, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesDepartment of Biological Sciences, Ohio University, Athens, OH, United StatesMolecular Cellular Biology Program, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesDepartment of Biological Sciences, Ohio University, Athens, OH, United StatesMolecular Cellular Biology Program, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesDepartment of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesEdison Biotechnology Institute, Ohio University, Athens, OH, United StatesMolecular Cellular Biology Program, Ohio University, Athens, OH, United StatesDepartment of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United StatesTranslational Biological Sciences Program, Ohio University, Athens, OH, United StatesKnockdown 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.https://www.frontiersin.org/articles/10.3389/fonc.2022.936145/fullgrowth hormone (GH)GHAgrowth hormone receptor antagonist (GHRA)melanomaHCCABC transporters |
| spellingShingle | Reetobrata Basu Yanrong Qian Samuel Mathes Joseph Terry Joseph Terry Nathan Arnett Nathan Arnett Trent Riddell Trent Riddell Austin Stevens Austin Stevens Kevin Funk Kevin Funk Kevin Funk Stephen Bell Stephen Bell Zac Bokal Courtney Batten Cole Smith Isaac Mendez-Gibson Silvana Duran-Ortiz Grace Lach Grace Lach Patricia Alexandra Mora-Criollo Prateek Kulkarni Prateek Kulkarni Prateek Kulkarni Emily Davis Emily Davis Emily Davis Elizabeth Teaford Darlene E. Berryman Darlene E. Berryman Edward O. List Sebastian Neggers John J. Kopchick John J. Kopchick John J. Kopchick John J. Kopchick Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo Frontiers in Oncology growth hormone (GH) GHA growth hormone receptor antagonist (GHRA) melanoma HCC ABC transporters |
| title | Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo |
| title_full | Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo |
| title_fullStr | Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo |
| title_full_unstemmed | Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo |
| title_short | Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo |
| title_sort | growth hormone receptor antagonism downregulates atp binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo |
| topic | growth hormone (GH) GHA growth hormone receptor antagonist (GHRA) melanoma HCC ABC transporters |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.936145/full |
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