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

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.

Growth Hormone Receptor Antagonist Markedly Improves Gemcitabine Response in a Mouse Xenograft Model of Human Pancreatic Cancer

“…In the present study, we observed a marked suppression of gemcitabine resistance in the presence of GHRAs. We have previously shown that GHR inhibition sensitizes melanoma cells to paclitaxel, as well as platinumbased antineoplastic drugs like cisplatin [64][65][66], and the pyrimidine analog fluorouracil (5-FU) (70). Therefore, based on our previous and current studies, GHRAs can potentially augment the current anti-PDAC chemotherapeutic combinations such as gemcitabine-paclitaxel, as well as FOLFIRINOX (combination of 5-FU, oxaliplatin, irinotecan, and folinic acid).…”

Structure and function of a dual antagonist of the human growth hormone and prolactin receptors with site-specific PEG conjugates

“…We and others have previously shown that hGH action in melanoma upregulates the epithelial-to-mesenchymal transition program ( via upregulation of expression of epithelial-to-mesenchymal transition–related transcription factors) in these cancer cells, thereby promoting their migration and invasion potential ( 45 , 46 , 47 , 48 , 49 , 50 ). Accordingly, the cell migration rate in the absence and presence of hGH was evaluated over a 48-h period including treatments with doxorubicin alone or in conjunction with the candidate GHR antagonists.…”

“…Human melanoma cells express a consistently high level of hGHR ( 44 ) and are highly responsive to hGH action, which regulates multiple oncogenic pathways and processes in this cancer ( 45 , 46 , 47 , 48 , 49 , 50 ). Therefore, a GHR antagonist is a candidate negative regulator of melanoma cell growth and therapeutic response.…”

Three E2F target-related genes signature for predicting prognosis, immune features, and drug sensitivity in hepatocellular carcinoma

“…Scholars from Texas MD Anderson Cancer observed that tumor cells exhibited slower growth and overcame sorafenib resistance by blocking GHR with pegvisomant in vitro ( Kaseb et al, 2022 ). GH inhibition downregulates ABC transporters and sensitizes HCC allografts to sorafenib ( Basu et al, 2022 ). We noted that GHR’s downregulation is associated with HCV-induced HCC ( Lin et al, 2021 ; Abu El-Makarem et al, 2022 ).…”