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Head and Neck Squamous Cell Carcinoma Metabolism Draws on Glutaminolysis, and Stemness Is Specifically Regulated by Glutaminolysis via Aldehyde Dehydrogenase
journal contribution
posted on 2017-02-07, 00:00 authored by Pachiyappan Kamarajan, Thekkelnaycke M. Rajendiran, Jason Kinchen, Mercedes Bermúdez, Theodora Danciu, Yvonne L. KapilaCancer
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/ALDHlo cells. Glutaminase drove transcriptional and translational
ALDH expression, and glutamine directed even CD44lo/ALDHlo cells 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.