Head and Neck Squamous Cell Carcinoma Metabolism Draws on Glutaminolysis, and Sternness Is Specifically Regulated by Glutaminolysis via Aldehyde Dehydrogenase
Por:
Kamarajan, Pachiyappan, Rajendiran, Thekkelnaycke M., Kinchen, Jason, Bermudez, Mercedes, Danciu, Theodora, Kapila, Yvonne L.
Publicada:
1 mar 2017
Resumen:
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 sternness marker, were
highly expressed in primary and metastatic head and neck cancer tissues,
tumorspheres, and CSC versus controls. Exogenous glutamine induced
sternness via glutaminase,. whereas inhibiting glutaminase suppressed
sternness in vitro and tumorigenesis in vivo. Head and neck CSC
(CD44(hi/)ALDH(hi) exhibited higher glutaminase, glutamate, and sphere
levels than CD44(lo)/ALDH(lo) cells. Glutaminase drove transcriptional
and translational ALDH expression, and glutamine directed even
CD44(lo)/ALDH(lo) cells toward sternness. 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.
Filiaciones:
Kamarajan, Pachiyappan:
Univ Calif San Francisco, UCSF Sch Dent, Dept Orofacial Sci, San Francisco, CA 94110 USA
Rajendiran, Thekkelnaycke M.:
Univ Michigan, Dept Pathol, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA
Univ Michigan, Michigan Reg Comprehens Metab Resource Core, Ann Arbor, MI 48109 USA
Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA
Kinchen, Jason:
Metabolon Inc, Durham, NC 27713 USA
Bermudez, Mercedes:
Univ Nacl Autonoma Mexico, FES Zaragoza, Mexico City 09320, DF, Mexico
Danciu, Theodora:
Univ Michigan, Sch Dent, Dept Periodont & Oral Med, Ann Arbor, MI 48109 USA
Kapila, Yvonne L.:
Univ Calif San Francisco, UCSF Sch Dent, Dept Orofacial Sci, San Francisco, CA 94110 USA
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