EGFR Signaling Enhances Aerobic Glycolysis in Triple-Negative Breast Cancer Cells to Promote Tumor Growth and Immune Escape.
EGFR Signaling Enhances Aerobic Glycolysis in Triple-Negative Breast Cancer Cells to Promote Tumor Growth and Immune Escape.
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DOI：
10.1158/0008-5472.can-15-2478
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发表时间：
2016-03-01
期刊：
影响因子：
11.2
通讯作者：
Hung MC
中科院分区：
文献类型：
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作者：
Lim SO;Li CW;Xia W;Lee HH;Chang SS;Shen J;Hsu JL;Raftery D;Djukovic D;Gu H;Chang WC;Wang HL;Chen ML;Huo L;Chen CH;Wu Y;Sahin A;Hanash SM;Hortobagyi GN;Hung MC
致癌性信号转导重新编程癌细胞代谢以增加糖酵解代谢物的产生，从而有利于肿瘤生长。癌细胞逃避免疫监视的能力和代谢调节因子在T细胞功能中的作用表明，癌基因诱导的代谢重编程可能与免疫逃逸有关。在三阴性乳腺癌（TNBC）中经常失调的表皮生长因子（EGF）信号传导也与糖酵解增加有关。在这里，我们在TNBC细胞中证明了EGF信号激活了糖酵解的第一步，但阻碍了最后一步，导致代谢中间产物在该途径中积累。此外，我们发现，这些中间体之一，果糖1，6二磷酸（F1，6 BP），直接结合并增强EGF受体（EGFR）的活性，从而增加乳酸排泄，导致抑制局部细胞毒性T细胞活性。值得注意的是，将糖酵解抑制剂2-脱氧-D-葡萄糖（2-DG）与EGFR抑制剂吉非替尼组合有效地抑制了TNBC细胞增殖和肿瘤生长。我们的研究结果说明了联合靶向EGFR/F1，6 BP信号传导轴可以提供立即适用的治疗策略来治疗TNBC。
Oncogenic signaling reprograms cancer cell metabolism to augment the production of glycolytic metabolites in favor of tumor growth. The ability of cancer cells to evade immunosurveillance and the role of metabolic regulators in T cell functions suggest that oncogene-induced metabolic reprogramming may be linked to immune escape. Epidermal growth factor (EGF) signaling, frequently dysregulated in triple-negative breast cancer (TNBC), is also associated with increased glycolysis. Here, we demonstrated in TNBC cells that EGF signaling activates the first step in glycolysis, but impedes the last step, leading to an accumulation of metabolic intermediates in this pathway. Furthermore, we showed that one of these intermediates, fructose 1,6 bisphosphate (F1,6BP), directly binds to and enhances the activity of the EGF receptor (EGFR), thereby increasing lactate excretion which leads to inhibition of local cytotoxic T cell activity. Notably, combining the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) with the EGFR inhibitor gefitinib effectively suppressed TNBC cell proliferation and tumor growth. Our results illustrate how jointly targeting the EGFR/F1,6BP signaling axis may offer an immediately applicable therapeutic strategy to treat TNBC.