NDUFS3 promotes proliferation via glucose metabolism reprogramming inducing AMPK phosphorylating PRPS1 to increase the purine nucleotide synthesis in melanoma

IF 13.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Death and Differentiation Pub Date : 2025-05-22 DOI:10.1038/s41418-025-01525-4

Guohang Xiong, Fang Yun, Lu Jiang, Zihan Yi, Xiaojia Yi, Lijuan Yang, Xuedan Zhang, Xiaoyu Li, Zhe Yang, Qiao Zhang, Buqing Sai, Yingmin Kuang, Yuechun Zhu

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Abstract

NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) is the core subunit of the respiratory chain complex I (CI). We found NDUFS3 were abnormally elevated in human melanoma and promoted melanoma proliferation. Furthermore, NDUFS3 could promote the oxidative phosphorylation (OXPHOS) and the pentose phosphate pathway (PPP), as well as attenuated glycolysis. As NDUFS3-mediated the metabolic changes of OXPHOS and glucose metabolism, melanoma cells produced more ATP, resulting in the inhibition of AMP kinase (AMPK). AMPK induced phosphoribosyl pyrophosphate synthetase1 (PRPS1) phosphorylation, which resulted in suppressed PRPS1 activity. Briefly, the NDUFS3-AMPK-PRPS1 signaling axis coupled OXPHOS, glucose metabolism, and purine nucleotide biosynthesis to regulate melanoma proliferation. Our study highlighted an unrecognized role for NDUFS3 in melanoma, which might be used as a potential therapeutic target for the treatment of this type of cancer.

NDUFS3 regulating PRPS1 activity through AMPK to affect melanoma proliferation.

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NDUFS3通过糖代谢重编程诱导AMPK磷酸化PRPS1，增加黑色素瘤嘌呤核苷酸合成，从而促进增殖

NADH脱氢酶[泛醌]铁硫蛋白3 （NDUFS3）是呼吸链复合体I （CI）的核心亚基。我们发现NDUFS3在人类黑色素瘤中异常升高，并促进黑色素瘤的增殖。此外，NDUFS3可以促进氧化磷酸化（OXPHOS）和戊糖磷酸途径（PPP），并减弱糖酵解。由于ndufs3介导OXPHOS和葡萄糖代谢的代谢变化，黑色素瘤细胞产生更多的ATP，导致AMP激酶（AMPK）的抑制。AMPK诱导磷酸核糖基焦磷酸合成酶1 （PRPS1）磷酸化，从而抑制PRPS1活性。简而言之，NDUFS3-AMPK-PRPS1信号轴耦合OXPHOS、葡萄糖代谢和嘌呤核苷酸生物合成来调节黑色素瘤的增殖。我们的研究强调了NDUFS3在黑色素瘤中未被认识到的作用，它可能被用作治疗这类癌症的潜在治疗靶点。NDUFS3通过AMPK调控PRPS1活性影响黑色素瘤增殖。

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来源期刊

Cell Death and Differentiation 生物-生化与分子生物学

CiteScore

24.70

自引率

1.60%

发文量

181

审稿时长

3 months

期刊介绍： Mission, vision and values of Cell Death & Differentiation: To devote itself to scientific excellence in the field of cell biology, molecular biology, and biochemistry of cell death and disease. To provide a unified forum for scientists and clinical researchers It is committed to the rapid publication of high quality original papers relating to these subjects, together with topical, usually solicited, reviews, meeting reports, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.