Growth Hormone Upregulates Melanoma Drug Resistance and Migration via Melanoma-Derived Exosomes
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Published on: March 29, 2024
Prateek Kulkarni1,2,3, Reetobrata Basu1, Taylor Bonn1,4
1Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.
Abstract:
Drug resistance in melanoma is a major hindrance in cancer therapy. Growth hormone (GH) plays a pivotal role in contributing to the resistance to chemotherapy. Knocking down or blocking the GH receptor has been shown to sensitize the tumor cells to chemotherapy. Extensive studies have demonstrated that exosomes, a subset of extracellular vesicles, play an important role in drug resistance by transferring key factors to sensitize cancer cells to chemotherapy. In this study, we explore how GH modulates exosomal cargoes from melanoma cells and their role in drug resistance. We treated the melanoma cells with GH, doxorubicin, and the GHR antagonist, pegvisomant, and analyzed the exosomes released. Additionally, we administered these exosomes to the recipient cells. The GH-treated melanoma cells released exosomes with elevated levels of ABC transporters (ABCC1 and ABCB1), N-cadherin, and MMP2, enhancing drug resistance and migration in the recipient cells. GHR antagonism reduced these exosomal levels, restoring drug sensitivity and attenuating migration. Overall, our findings highlight a novel role of GH in modulating exosomal cargoes that drive chemoresistance and metastasis in melanoma. This understanding provides insights into the mechanisms of GH in melanoma chemoresistance and suggests GHR antagonism as a potential therapy to overcome chemoresistance in melanoma treatment.
Insights
Growth hormone (GH) drives melanoma chemoresistance by altering exosome contents, increasing drug resistance and metastasis. Blocking the GH receptor (GHR) with pegvisomant reverses these effects, restoring drug sensitivity and reducing melanoma spread.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Melanoma drug resistance poses a significant challenge in cancer therapy.
- Growth hormone (GH) is implicated in promoting chemotherapy resistance.
- Exosomes mediate drug resistance by transferring specific molecules between cells.
Purpose of the Study:
- To investigate how GH influences exosome composition in melanoma cells.
- To determine the role of GH-modulated exosomes in melanoma chemoresistance and metastasis.
- To evaluate the therapeutic potential of GHR antagonism in overcoming melanoma drug resistance.
Main Methods:
- Melanoma cells were treated with GH, doxorubicin, and the GHR antagonist pegvisomant.
- Exosomes released from treated cells were isolated and analyzed for cargo.
- Recipient cells were treated with these exosomes to assess effects on drug sensitivity and migration.
Main Results:
- GH treatment increased exosomal levels of ABC transporters (ABCC1, ABCB1), N-cadherin, and MMP2.
- These GH-induced exosomal changes enhanced drug resistance and migration in recipient melanoma cells.
- GHR antagonism with pegvisomant reduced these exosomal alterations, improving drug sensitivity and decreasing migration.
Conclusions:
- GH modulates exosomal cargoes in melanoma, contributing to chemoresistance and metastasis.
- GHR antagonism represents a potential therapeutic strategy to combat melanoma drug resistance.
- Understanding GH's role in exosome-mediated resistance offers new avenues for melanoma treatment.
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