HPV E6 regulates therapy responses in oropharyngeal cancer by repressing the PGC-1α/ERRα axis.
HPV E6 regulates therapy responses in oropharyngeal cancer by repressing the PGC-1α/ERRα axis.
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HPV E6通过抑制PGC-1α/ERRα轴来调节口咽癌的治疗反应。
DOI：
10.1172/jci.insight.159600
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发表时间：
2022-09-22
期刊：
影响因子：
8
通讯作者：
Basu, Devraj
中科院分区：
文献类型：
--
作者：
Sannigrahi, Malay K.;Rajagopalan, Pavithra;Lai, Ling;Liu, Xinyi;Sahu, Varun;Nakagawa, Hiroshi;Jalaly, Jalal B.;Brody, Robert M.;Morgan, Iain M.;Windle, Bradford E.;Wang, Xiaowei;Gimotty, Phyllis A.;Kelly, Daniel P.;White, Elizabeth A.;Basu, Devraj
放疗加顺铂治疗通过增加活性氧超过细胞抗氧化能力杀死HPV+口咽鳞状细胞癌（OPSCC）。为了探索为什么这些标准治疗对某些患者无效，我们评估了HPV+ OPSCC中HPV癌蛋白水平的变化是否影响线粒体代谢，这是抗氧化能力的来源。在细胞系和患者来源的异种移植物模型中，HPV全长E6（fl-E6）的水平与氧化磷酸化、抗氧化能力和治疗抗性负相关，并且fl-E6是唯一显示这种相关性的HPV癌蛋白。在具有低基线水平的模型中异位表达fl-E6降低了线粒体质量，耗尽了抗氧化能力，并对治疗敏感。在这种情况下，fl-E6通过减少p53依赖性PGC-1α转录来抑制线粒体生物合成的过氧化物酶体增殖物激活受体γ共激活因子1α/雌激素相关受体α（PGC-1α/ERRα）途径。在3个临床队列中进行了一致的观察，其中线粒体组分的表达在存活率降低的患者的肿瘤中更高。这些肿瘤含有最低的fl-E6水平、最高的p53靶基因表达和激活的PGC-1α/ERRα通路。我们的研究结果表明，E6可以通过消耗线粒体抗氧化能力来增强治疗反应，并为低E6对患者生存率产生负面影响提供证据。E6与PGC-1α/ERRα轴的相互作用对预测和靶向OPSCC的治疗耐药性具有意义。
Therapy with radiation plus cisplatin kills HPV+ oropharyngeal squamous cell carcinomas (OPSCCs) by increasing reactive oxygen species beyond cellular antioxidant capacity. To explore why these standard treatments fail for some patients, we evaluated whether the variation in HPV oncoprotein levels among HPV+ OPSCCs affects mitochondrial metabolism, a source of antioxidant capacity. In cell line and patient-derived xenograft models, levels of HPV full-length E6 (fl-E6) inversely correlated with oxidative phosphorylation, antioxidant capacity, and therapy resistance, and fl-E6 was the only HPV oncoprotein to display such correlations. Ectopically expressing fl-E6 in models with low baseline levels reduced mitochondrial mass, depleted antioxidant capacity, and sensitized to therapy. In this setting, fl-E6 repressed the peroxisome proliferator–activated receptor gamma co-activator 1α/estrogen-related receptor α (PGC-1α/ERRα) pathway for mitochondrial biogenesis by reducing p53-dependent PGC-1α transcription. Concordant observations were made in 3 clinical cohorts, where expression of mitochondrial components was higher in tumors of patients with reduced survival. These tumors contained the lowest fl-E6 levels, the highest p53 target gene expression, and an activated PGC-1α/ERRα pathway. Our findings demonstrate that E6 can potentiate treatment responses by depleting mitochondrial antioxidant capacity and provide evidence for low E6 negatively affecting patient survival. E6’s interaction with the PGC-1α/ERRα axis has implications for predicting and targeting treatment resistance in OPSCC.
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DOI：
10.1073/pnas.0705070104
发表时间：
2007-07-17
影响因子：
11.1
作者：
Jaeger, Sibylle;Handschin, Christoph;Spiegelman, Bruce M.
通讯作者：
Spiegelman, Bruce M.
影响因子：
11.2
作者：
Guo T;Sakai A;Afsari B;Considine M;Danilova L;Favorov AV;Yegnasubramanian S;Kelley DZ;Flam E;Ha PK;Khan Z;Wheelan SJ;Gutkind JS;Fertig EJ;Gaykalova DA;Califano J
通讯作者：
Califano J
影响因子：
6.4
作者：
Facompre ND;Rajagopalan P;Sahu V;Pearson AT;Montone KT;James CD;Gleber-Netto FO;Weinstein GS;Jalaly J;Lin A;Rustgi AK;Nakagawa H;Califano JA;Pickering CR;White EA;Windle BE;Morgan IM;Cohen RB;Gimotty PA;Basu D
通讯作者：
Basu D
影响因子：
10.5
作者：
Basu S;Gnanapradeepan K;Barnoud T;Kung CP;Tavecchio M;Scott J;Watters A;Chen Q;Kossenkov AV;Murphy ME
通讯作者：
Murphy ME
影响因子：
8.8
作者：
Aguilo F;Li S;Balasubramaniyan N;Sancho A;Benko S;Zhang F;Vashisht A;Rengasamy M;Andino B;Chen CH;Zhou F;Qian C;Zhou MM;Wohlschlegel JA;Zhang W;Suchy FJ;Walsh MJ
通讯作者：
Walsh MJ