Joshi Abhinav, Dai Li, Maisiak Marisa, Lee Sunmin, Lopez Elizabeth, Ito Takeshi, Neckers Len
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Mol Cancer Res. 2025 Sep 4;23(9):792-806. doi: 10.1158/1541-7786.MCR-24-0194.
TRAP1, the mitochondrial isoform of HSP90, has emerged as a key regulator of cancer cell metabolism, yet the mechanisms by which it rewires nutrient utilization remain poorly understood. We previously reported that TRAP1 loss increases glutamine (Gln) dependency of mitochondrial respiration following glucose (Glc) withdrawal. In this study, we investigate how TRAP1 deletion impacts Glc metabolism and the mechanisms enabling Gln retention to support mitochondrial respiration via reductive carboxylation and the oxidative TCA cycle. TRAP1 knockout (KO) in bladder and prostate cancer cells recapitulates the carbon source-specific metabolic rewiring previously observed. Stable isotope tracing reveals that although Glc oxidation remains functional, TRAP1 KO reduces overall Glc uptake and its contribution to glycolysis and the pentose phosphate pathway. This effect is consistent across multiple cell lines. Concurrently, TRAP1-deficient cells exhibit increased Gln retention and reliance, potentially due to downregulation of the cystine/glutamate antiporter SLC7A11/xCT. Supporting this, xCT overexpression reduces Gln-dependent respiration in TRAP1 KO cells. qPCR and proteasome inhibition assays suggest that xCT is regulated posttranslationally via protein stability. Notably, xCT suppression does not trigger ferroptosis, indicating a selective adaptation rather than induction of cell death. Together, our findings suggest that TRAP1 loss decreases Glc uptake while preserving its metabolic fate, promoting Gln conservation through xCT downregulation to maintain mitochondrial respiration without inducing ferroptosis.
These results reveal a TRAP1-dependent mechanism of metabolic rewiring in cancer cells and identify xCT-mediated Gln conservation as a key adaptive response, underscoring TRAP1 as a potential metabolic vulnerability and therapeutic target in tumors with altered nutrient utilization.
热休克蛋白90（HSP90）的线粒体异构体TRAP1已成为癌细胞代谢的关键调节因子，但其重新连接营养物质利用的机制仍知之甚少。我们之前报道过，TRAP1缺失会增加葡萄糖（Glc）撤出后线粒体呼吸对谷氨酰胺（Gln）的依赖性。在本研究中，我们探究TRAP1缺失如何影响Glc代谢，以及通过还原羧化作用和氧化三羧酸（TCA）循环使Gln保留以支持线粒体呼吸的机制。膀胱癌细胞和前列腺癌细胞中的TRAP1基因敲除（KO）重现了先前观察到的碳源特异性代谢重布线。稳定同位素示踪显示，尽管Glc氧化仍起作用，但TRAP1基因敲除会降低总体Glc摄取及其对糖酵解和磷酸戊糖途径的贡献。这种效应在多个细胞系中是一致的。同时，TRAP1缺陷型细胞表现出Gln保留和依赖性增加，这可能是由于胱氨酸/谷氨酸反向转运蛋白SLC7A11/xCT的下调。支持这一观点的是，xCT过表达降低了TRAP1基因敲除细胞中对Gln的依赖性呼吸。定量聚合酶链反应（qPCR）和蛋白酶体抑制试验表明，xCT是通过蛋白质稳定性在翻译后受到调控的。值得注意的是，xCT抑制不会引发铁死亡，表明这是一种选择性适应而非诱导细胞死亡。总之，我们的研究结果表明，TRAP1缺失会降低Glc摄取，同时保留其代谢命运，通过下调xCT促进Gln保留以维持线粒体呼吸而不诱导铁死亡。
这些结果揭示了癌细胞中一种依赖TRAP1的代谢重布线机制，并将xCT介导的Gln保留确定为一种关键的适应性反应，强调TRAP1是营养物质利用改变的肿瘤中潜在的代谢脆弱点和治疗靶点。
