PO.MCB07.03 · 分子与细胞生物学
靶向SLC25A13通过代谢重编程使黑色素瘤对治疗敏感并降低肿瘤侵袭性
Targeting SLC25A13 sensitizes melanoma to treatment and reduces tumor aggressiveness via metabolic rewiring
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
治疗耐药是黑色素瘤治疗的主要挑战之一，促使人们研究新的治疗靶点以阐明新颖的治疗方法和分子见解。在这项黑色素瘤研究中，我们探讨了SLC25A13的作用，该基因在人类中编码citrin，一种线粒体载体蛋白，在代谢性疾病中具有明确表征的功能。我们证明肿瘤中SLC25A13上调与两个具有长期随访的大型黑色素瘤队列中的不良生存相关。功能试验揭示SLC25A13的过表达改变关键代谢物的水平，导致一种类似代谢综合征的状态，这对转移性黑色素瘤细胞的存活至关重要。我们提出SLC25A13作为一个关键的代谢节点，通过增强增殖、侵袭和肿瘤进展来促进黑色素瘤的侵袭性。值得注意的是，我们展示在侵袭性小鼠黑色素瘤细胞中沉默Slc25a13使它们对达卡巴嗪和MEK抑制均敏感，凸显了其作为治疗靶点的潜力。因此，SLC25A13是一个关键的生物标志物，也是克服转移性黑色素瘤治疗耐药的有前景的靶点。
查看英文原文 English abstract
Therapy resistance is one of the main challenges for melanoma treatment, prompting the investigation of new therapeutic targets to elucidate novel therapeutic approaches and molecular insights. In this melanoma study, we have investigated the role of SLC25A13 which in humans encodes citrin, a mitochondrial carrier protein with a well-characterized function in metabolic diseases. We demonstrated that SLC25A13 upregulation in tumors is associated with poor survival in two large melanoma cohorts with long follow-up. Functional assays revealed that overexpression of SLC25A13 alters the level of key metabolites, leading to a metabolic syndrome-like state that is essential for the survival of metastatic melanoma cells. We propose that SLC25A13 functions as a key metabolic node promoting melanoma aggressiveness by enhancing proliferation, invasion, and tumor progression. Notably, we show that silencing Slc25a13 in aggressive mouse melanoma cells sensitizes them to both dacarbazine and MEK inhibition, highlighting its potential as a therapeutic target. Thus SLC25A13 is a key biomarker and a promising target for overcoming therapy resistance in metastatic melanoma.
利益披露 Disclosure
B. C. B. Tonin, None..
A. P. Auyb, None..
J. Nsengimana, None..
H. Azevedo, None..
B. Kopel, None..
N. Souza-Pinto, None..
F. J. Slack, None..
M. G. Jasiulionis, None.