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H(2)S-induced S-sulfhydration of lactate dehydrogenase a (LDHA) stimulates
cellular bioenergetics in HCT116 colon cancer cells
#MMPMID28404377
Untereiner AA
; Oláh G
; Módis K
; Hellmich MR
; Szabo C
Biochem Pharmacol
2017[Jul]; 136
(?): 86-98
PMID28404377
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Cystathionine-?-synthase (CBS) is upregulated and hydrogen sulfide (H(2)S)
production is increased in colon cancer cells. The functional consequence of this
response is stimulation of cellular bioenergetics and tumor growth and
proliferation. Lactate dehydrogenase A (LDHA) is also upregulated in various
colon cancer cells and has been previously implicated in tumor cell bioenergetics
and proliferation. In the present study, we sought to determine the potential
interaction between the H(2)S pathway and LDH activity in the control of
bioenergetics and proliferation of colon cancer, using the colon cancer line
HCT116. Low concentrations of GYY4137 (a slow-releasing H(2)S donor) enhanced
mitochondrial function (oxygen consumption, ATP production, and spare respiratory
capacity) and glycolysis in HCT116 cells. SiRNA-mediated transient silencing of
LDHA attenuated the GYY4137-induced stimulation of mitochondrial respiration, but
not of glycolysis. H(2)S induced the S-sulfhydration of Cys163 in recombinant
LDHA, and stimulated LDHA activity. The H(2)S-induced stimulation of LDHA
activity was absent in C163A LDHA. As shown in HCT116 cell whole extracts, in
addition to LDHA activation, GYY4137 also stimulated LDHB activity, although to a
smaller extent. Total cellular lactate and pyruvate measurements showed that in
HCT116 cells LDHA catalyzes the conversion of pyruvate to lactate. Total cellular
lactate levels were increased by GYY4137 in wild-type cells (but not in cells
with LDHA silencing). LDHA silencing sensitized HCT116 cells to glucose oxidase
(GOx)-induced oxidative stress; this was further exacerbated with GYY4137
treatment. Treatment with low concentrations of GYY4137 (0.3mM) or GOx (0.01U/ml)
significantly increased the proliferation rate of HCT116 cells; the effect of
GOx, but not the effect of GYY4137 was attenuated by LDHA silencing. The current
report points to the involvement of LDHA in the stimulatory effect of H(2)S on
mitochondrial respiration in colon cancer cells and characterizes some of the
functional interactions between LDHA and H(2)S-stimulated bioenergetics under
resting conditions, as well as during oxidative stress.
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