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.
黑色素瘤中的耐药性是癌症治疗的主要障碍。生长激素在促进化疗耐药性方面起着关键作用。研究表明，敲低或阻断生长激素受体可使肿瘤细胞对化疗药物更敏感。大量研究证实，外泌体作为细胞外囊泡的一个亚群，通过传递关键因子使癌细胞对化疗敏感，在耐药性形成中发挥重要作用。本研究探讨了生长激素如何调节黑色素瘤细胞外泌体内容物及其在耐药性中的作用。我们使用生长激素、阿霉素和生长激素受体拮抗剂培维索孟处理黑色素瘤细胞，并分析其释放的外泌体。此外，我们将这些外泌体作用于受体细胞。经生长激素处理的黑色素瘤细胞释放的外泌体中，ABC转运蛋白（ABCC1和ABCB1）、N-钙黏蛋白及MMP2水平升高，从而增强了受体细胞的耐药性和迁移能力。而生长激素受体拮抗作用降低了这些外泌体内容物水平，恢复了药物敏感性并减弱了细胞迁移。总体而言，我们的研究结果揭示了生长激素在调节外泌体内容物方面的新作用，这些内容物驱动了黑色素瘤的化疗耐药和转移。这一认识为理解生长激素在黑色素瘤化疗耐药中的作用机制提供了新视角，并提示生长激素受体拮抗可能成为克服黑色素瘤治疗中化疗耐药性的潜在疗法。
Growth Hormone Upregulates Melanoma Drug Resistance and Migration via Melanoma-Derived Exosomes
肿瘤(癌症)患者之家