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2017 ; 16
(1
): 51
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Regulation of stem-like cancer cells by glutamine through ?-catenin pathway
mediated by redox signaling
#MMPMID28245869
Liao J
; Liu PP
; Hou G
; Shao J
; Yang J
; Liu K
; Lu W
; Wen S
; Hu Y
; Huang P
Mol Cancer
2017[Feb]; 16
(1
): 51
PMID28245869
show ga
BACKGROUND: Cancer stem cells (CSCs) are thought to play an important role in
tumor recurrence and drug resistance, and present a major challenge in cancer
therapy. The tumor microenvironment such as growth factors, nutrients and oxygen
affect CSC generation and proliferation by providing the necessary energy sources
and growth signals. The side population (SP) analysis has been used to detect the
stem-like cancer cell populations based on their high expression of ABCG2 that
exports Hoechst-33342 and certain cytotoxic drugs from the cells. The purpose of
this research is to investigate the effect of a main nutrient molecule,
glutamine, on SP cells and the possible underlying mechanism(s). METHODS:
Biochemical assays and flow cytometric analysis were used to evaluate the effect
of glutamine on stem-like side population cells in vitro. Molecular analyses
including RNAi interfering, qRT-PCR, and immunoblotting were employed to
investigate the molecular signaling in response to glutamine deprivation and its
influence on tumor formation capacity in vivo. RESULTS: We show that glutamine
supports the maintenance of the stem cell phenotype by promoting glutathione
synthesis and thus maintaining redox balance for SP cells. A deprivation of
glutamine in the culture medium significantly reduced the proportion of SP cells.
L-asparaginase, an enzyme that catalyzes the hydrolysis of asparagine and
glutamine to aspartic acid and glutamate, respectively, mimics the effect of
glutamine withdrawal and also diminished the proportion of SP cells.
Mechanistically, glutamine deprivation increases intracellular ROS levels,
leading to down-regulation of the ?-catenin pathway. CONCLUSION: Glutamine plays
a significant role in maintaining the stemness of cancer cells by a
redox-mediated mechanism mediated by ?-catenin. Inhibition of glutamine
metabolism or deprivation of glutamine by L-asparaginase may be a new strategy to
eliminate CSCs and overcome drug resistance.
|A549 Cells
[MESH]
|ATP Binding Cassette Transporter, Subfamily G, Member 2/*metabolism
[MESH]