PDF(Pubmed)
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.
摘要：
黑色素瘤的耐药性是癌症治疗的主要障碍。生长激素(GH)在化疗耐药中起关键作用。已经证明敲除或阻断GH受体会使肿瘤细胞对化疗敏感。广泛的研究表明，外泌体，细胞外囊泡的一个子集，通过转移关键因素使癌细胞对化疗敏感，在耐药中起重要作用。在这项研究中,我们探讨GH如何调节黑色素瘤细胞的外泌体及其在耐药性中的作用。我们用GH治疗黑色素瘤细胞，阿霉素,和GHR拮抗剂，pegvisomant,并分析了释放的外泌体。此外,我们将这些外泌体给予受体细胞。GH处理的黑色素瘤细胞释放外泌体，ABC转运蛋白（ABCC1和ABCB1）水平升高，N-钙黏着蛋白,和MMP2，增强了受体细胞的耐药性和迁移。GHR拮抗作用降低了这些外泌体水平，恢复药物敏感性和减少迁移。总的来说,我们的研究结果强调了GH在调节外泌体载体中的一个新的作用,这些载体驱动黑色素瘤的化学耐药和转移.这种理解提供了对GH在黑色素瘤化学抗性中的机制的见解，并表明GHR拮抗作用是克服黑色素瘤治疗中的化学抗性的潜在疗法。
