A positive feedback loop involving EGFR/Akt/mTORC1 and IKK/NF-kB regulates head and neck squamous cell carcinoma proliferation.
A positive feedback loop involving EGFR/Akt/mTORC1 and IKK/NF-kB regulates head and neck squamous cell carcinoma proliferation.
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DOI：
10.18632/oncotarget.7441
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发表时间：
2016-05-31
期刊：
影响因子：
--
通讯作者：
Dan HC
中科院分区：
文献类型：
--
作者：
Li Z;Yang Z;Passaniti A;Lapidus RG;Liu X;Cullen KJ;Dan HC
表皮生长因子受体（EGFR）的过度表达或突变与许多癌症有关，包括头颈鳞状细胞癌（HNSCC）。越来越多的证据表明，雷帕霉素的磷脂酰肌醇-3-激酶 (PI3K)-Akt-哺乳动物靶标 (mTOR) 和核因子-κ B (NF-κB) 均具有持续活性，并有助于 EGFR 下游的侵袭性 HNSCC。然而，这两种致癌信号通路在 HNSCC 中是否表现出分子和功能串扰尚不清楚。我们的结果现在表明，mTORC1（而不是 mTORC2）有助于 EGFR/PI3K/Akt 信号传导下游的 NF-κB 激活。从机制上讲，mTORC1 增强核因子 kappa-B 激酶 (IKK) 抑制剂的活性，从而加速 NF-κB 信号传导。同时，激活的 NF-κB/IKK 通过正反馈调节上调 EGFR 表达。新型 IKKβ 特异性抑制剂 CmpdA 阻断 NF-κB/IKK 活性，可显着抑制细胞增殖并诱导细胞凋亡。 CmpdA 还可使内在顺铂耐药的 HNSCC 细胞对顺铂治疗敏感。我们的研究结果揭示了 EGFR/PI3K/Akt/mTOR 信号传导促进头颈癌进展的新机制，并强调需要开发一种针对 IKK/NF-κB 的治疗策略，无论是作为单一药物还是与顺铂联合治疗头颈癌。
The overexpression or mutation of epidermal growth factor receptor (EGFR) has been associated with a number of cancers, including head and neck squamous cell carcinoma (HNSCC). Increasing evidence indicates that both the phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of Rapamycin (mTOR) and the nuclear factor-kappa B (NF-κB) are constitutively active and contribute to aggressive HNSCC downstream of EGFR. However, whether these two oncogenic signaling pathways exhibit molecular and functional crosstalk in HNSCC is unclear. Our results now reveal that mTORC1, not mTORC2, contributes to NF-κB activation downstream of EGFR/PI3K/Akt signaling. Mechanistically, mTORC1 enhances the inhibitor of nuclear factor kappa-B kinase (IKK) activity to accelerate NF-κB signaling. Concomitantly, activated NF-κB/IKK up-regulates EGFR expression through positive feedback regulation. Blockage of NF-κB/IKK activity by the novel IKKβ specific inhibitor, CmpdA, leads to significant inhibition of cell proliferation and induction of apoptosis. CmpdA also sensitizes intrinsic cisplatin-resistant HNSCC cells to cisplatin treatment. Our findings reveal a new mechanism by which EGFR/PI3K/Akt/mTOR signaling promotes head and neck cancer progression and underscores the need for developing a therapeutic strategy for targeting IKK/NF-κB either as a single agent or in combination with cisplatin in head and neck cancer.
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