A positive feedback loop involving EGFR/Akt/mTORC1 and IKK/NF-kB regulates head and neck squamous cell carcinoma proliferation.

// Zhipeng Li 1 , Zejia Yang 1 , Antonino Passaniti 1, 2 , Rena G. Lapidus 1 , Xuefeng Liu 3 , Kevin J. Cullen 1 , Han C. Dan 1, 2 1 The Marlene & Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA 2 Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA 3 Department of Pathology, Georgetown University Medical Center, Washington, DC, USA Correspondence to: Han C. Dan, email: HDan@som.umaryland.edu Keywords: head and neck cancer, IKK, NF-kappaB, mTOR, Akt Received: October 15, 2015      Accepted: February 05, 2016      Published: February 17, 2016 ABSTRACT 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.