Study Shows Importance of mTORC1 and p21 Signaling in Head and Neck Carcinomas

A team of Spanish cancer researchers has found that over-activation of the mTORC1/4E-BP1/p21 molecular pathway is a frequent and clinically relevant alteration in head and neck squamous cell carcinomas (HNSCC).

Investigators at Centro Nacional de Investigaciones Oncologicas (Madrid, Spain) and the Central University Hospital of Asturias (Spain) analyzed more than 270 biopsies of patients with head and neck cancers and found that about half of them showed high levels of p21 protein as well as mTOR activation.

The p21 (cyclin-dependent kinase inhibitor 1) protein is a potent cyclin-dependent kinase inhibitor, which binds to and inhibits the activity of cyclin-CDK2, -CDK1, and -CDK4/6 complexes, and thus functions as a regulator of cell cycle progression at G1 and S phase. In addition to growth arrest, p21 can mediate cellular senescence. The expression of the CDKN1A gene, which encodes p21, is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli.

Mammalian target of rapamycin (mTOR) is a master regulator of protein synthesis that under ordinary conditions induces cells to grow and divide. However, in cancer cells the mTOR pathway does not function correctly and signals tumor cells to grow, divide, undergo metastasis, and invade new, healthy tissues. Functionally, mTOR is the catalytic subunit of two structurally distinct complexes: mTORC1 and mTORC2. Both complexes localize to different subcellular compartments, thus affecting their activation and function. MTORC1 is composed of the proteins mTOR, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8), and the non-core components PRAS40 and DEPTOR. This complex functions as a nutrient/energy/redox sensor and controls protein synthesis. The activity of mTORC1 is stimulated by insulin, growth factors, serum, phosphatidic acid, amino acids (particularly leucine), and oxidative stress.

In the current study, the investigators described a new mechanism of regulation of p21 by the mTORC1/4E-BP1 pathway. The 4E-BP1 gene encodes eukaryotic translation initiation factor 4E-binding protein 1, which is a member of a family of translation repressor proteins. The protein directly interacts with eukaryotic translation initiation factor 4E (eIF4E), which is a limiting component of the multi-subunit complex that recruits 40S ribosomal subunits to the 5' end of mRNAs. Interaction of this protein with eIF4E inhibits complex assembly and represses translation. This protein is phosphorylated in response to various signals including UV irradiation and insulin signaling, resulting in its dissociation from eIF4E and activation of cap-dependent mRNA translation.

The current study showed that non-phosphorylated 4E-BP1 interacted with p21 and induced its degradation. Accordingly, hyper-activation of mTORC1 resulted in phosphorylation of 4E-BP1 and stabilization of p21. In HNSCC, p21 levels strongly correlated with mTORC1 activity but not with p53 status. Clinical data indicated that HNSCC patients with p21 and phospho-S6-double-positive tumors presented a better disease-specific survival.

"One problem is the stratification of patients, which in many cases is limited to a clinical classification, not a molecular one," said contributing authors Dr. Susana Llanos and Dr. Juana M. García-Pedrero, researchers at Centro Nacional de Investigaciones Oncologicas and the Central University Hospital of Asturias, respectively.

The study was published in the February 2, 2016, online edition of the journal Nature Communications.

Related Links:
Centro Nacional de Investigaciones Oncologicas
Central University Hospital of Asturias