Head and Neck Squamous Cell Carcinoma Metabolism Draws on Glutaminolysis, and Stemness Is Specifically Regulated by Glutaminolysis via Aldehyde Dehydrogenase.
Cancer cells use alternate energetic pathways; however, cancer stem cell (CSC) metabolic energetic pathways are unknown. The purpose of this study was to define the metabolic characteristics of head and neck cancer at different points of its pathogenesis with a focus on its CSC compartment. UPLC-MS/MS-profiling and GC-MS-validation studies of human head and neck cancer tissue, saliva, and plasma were used in conjunction with in vitro and in vivo models to carry out this investigation. We identified metabolite biomarker panels that distinguish head and neck cancer from healthy controls, and confirmed involvement of glutamate and glutaminolysis. Glutaminase, which catalyzes glutamate formation from glutamine, and aldehyde dehydrogenase (ALDH), a stemness marker, were highly expressed in primary and metastatic head and neck cancer tissues, tumorspheres, and CSC versus controls. Exogenous glutamine induced stemness via glutaminase, whereas inhibiting glutaminase suppressed stemness in vitro and tumorigenesis in vivo. Head and neck CSC (CD44hi/ALDHhi) exhibited higher glutaminase, glutamate, and sphere levels than CD44lo/ALDHlocells. Glutaminase drove transcriptional and translational ALDH expression, and glutamine directed even CD44lo/ALDHlocells toward stemness. Glutaminolysis regulates tumorigenesis and CSC metabolism via ALDH. These findings indicate that glutamate is an important marker of cancer metabolism whose regulation via glutaminase works in concert with ALDH to mediate cancer stemness. Future analyses of glutaminolytic-ALDH driven mechanisms underlying tumorigenic transitions may help in the development of targeted therapies for head and neck cancer and its CSC compartment.
Department of Orofacial Sciences, UCSF School of Dentistry, University of California, San Francisco , California 94110, United States.
Pachiyappan
P
Kamarajan
Thekkelnaycke M
TM
Rajendiran
Metabolon, Inc. , Durham, North Carolina 27713, United States.
Jason
J
Kinchen
FES Zaragoza, National Autonomous University of Mexico , Mexico City, 09320, Mexico.
Mercedes
M
Bermúdez
Theodora
T
Danciu
Department of Orofacial Sciences, UCSF School of Dentistry, University of California, San Francisco , California 94110, United States.
Yvonne L
0000-0003-1330-0654
YL
Kapila
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D018698:Glutamic Acid; D005972:Glutaminase; D005973:Glutamine / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D053719:Tandem Mass Spectrometry
D005973:Glutamine; D018698:Glutamic Acid; D000444:Aldehyde Dehydrogenase; D005972:Glutaminase
cancer stem cells; glutamic acid; glutaminolysis; head and neck squamous cell carcinoma; metabolomics; stemness; tumorigenesis