ABSTRACT
PURPOSE: The heavy chain of the CD98 protein (CD98hc) is encoded by the SLC3A2 gene. Together with the light subunit LAT1, CD98hc constitutes a heterodimeric transmembrane amino acid transporter. High SLC3A2 mRNA expression levels are associated with poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC) treated with radiochemotherapy. Little is known regarding the CD98hc protein-mediated molecular mechanisms of tumor radioresistance. EXPERIMENTAL DESIGN: CD98hc protein expression levels were correlated with corresponding tumor control dose 50 (TCD50) in HNSCC xenograft models. Expression levels of CD98hc and LAT1 in HNSCC cells were modulated by siRNA or CRISPR/Cas9 gene editing. HNSCC cell phenotypes were characterized by transcription profiling, plasma membrane proteomics, metabolic analysis, and signaling pathway activation. Expression levels of CD98hc and LAT1 proteins were examined by IHC analysis of tumor tissues from patients with locally advanced HNSCC treated with primary radiochemotherapy (RCTx). Primary endpoint was locoregional tumor control (LRC). RESULTS: High expression levels of CD98hc resulted in an increase in mTOR pathway activation, amino acid metabolism, and DNA repair as well as downregulation of oxidative stress and autophagy. High expression levels of CD98hc and LAT1 proteins were significantly correlated and associated with an increase in radioresistance in HNSCC in vitro and in vivo models. High expression of both proteins identified a poor prognosis subgroup in patients with locally advanced HNSCC after RCTx. CONCLUSIONS: We found that CD98hc-associated signaling mechanisms play a central role in the regulation of HNSCC radioresistance and may be a promising target for tumor radiosensitization.
Subject(s)
Fusion Regulatory Protein 1, Heavy Chain/genetics , Radiation Tolerance/genetics , Squamous Cell Carcinoma of Head and Neck/genetics , Amino Acids/metabolism , Biological Transport , Biomarkers, Tumor , Cell Line, Tumor , Chemoradiotherapy , Citric Acid Cycle , Fusion Regulatory Protein 1, Heavy Chain/metabolism , Gene Expression , Gene Knockdown Techniques , Humans , Immunohistochemistry , Large Neutral Amino Acid-Transporter 1/genetics , Large Neutral Amino Acid-Transporter 1/metabolism , Oxidative Stress/genetics , Squamous Cell Carcinoma of Head and Neck/mortality , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/radiotherapyABSTRACT
The phospholipase C (PLC) enzymes are important regulators of membrane phospholipid metabolism. PLC proteins can be activated by the receptor tyrosine kinases (RTK) or G-protein coupled receptors (GPCR) in response to the different extracellular stimuli including hormones and growth factors. Activated PLC enzymes hydrolyze phosphoinositides to increase the intracellular level of Ca2+ and produce diacylglycerol, which are important mediators of the intracellular signaling transduction. PLC family includes 13 isozymes belonging to 6 subfamilies according to their domain structures and functions. Although importance of PLC enzymes for key cellular functions is well established, the PLC proteins belonging to the ε, ζ and η subfamilies were identified and characterized only during the last decade. As a largest known PLC protein, PLCε is involved in a variety of signaling pathways and controls different cellular properties. Nevertheless, its role in carcinogenesis remains elusive. The aim of this review is to provide a comprehensive and up-to-date overview of the experimental and clinical data about the role of PLCε in the development and progression of the different types of human and experimental tumors.
ABSTRACT
Metastatic tumors are the cause of more than 90% of cancer related deaths. Metastasis formation can be considered as a culmination of the Darwinian evolutionary process within the tumor, when competition of multiple clones results in the development of cell inherent traits that favor tumor dissemination. Cancer stem cells (CSC) which possess self-renewal properties and genomic instability are considered to be an engine of tumor evolution. Cancer cells which have the capacity to colonize distant organs have the features of CSC and, in addition, exert their tumor-initiating capacity under adverse microenvironmental conditions. Recent studies support an idea that metastases can be driven by the evolved and selected subpopulations of CSC. In this review we discuss the common hallmarks of CSC and metastasis initiating cells (MIC) and prospects for the development of anti-metastatic therapy.
