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2017 ; 8
(20
): 32576-32585
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NADPH accumulation is responsible for apoptosis in breast cancer cells induced by
fatty acid synthase inhibition
#MMPMID28427229
Cui Y
; Xing P
; Wang Y
; Liu M
; Qiu L
; Ying G
; Li B
Oncotarget
2017[May]; 8
(20
): 32576-32585
PMID28427229
show ga
Fatty acid synthase (FAS), as a key enzyme involved in de novo lipogenesis, is
highly expressed in many cancers. FAS inhibition induces cell death in vivo and
in vitro, rendering FAS as an attractive target for cancer therapy, but the
defined mechanism is still not well understood. Herein, we confirmed that FAS was
highly expressed in breast cancers and FAS inhibition by its inhibitors or
knockdown induced apoptosis in breast cancer cells. Our results showed that a
significantly high level of reactive oxygen species was induced but not
responsible for apoptosis in breast cancer cells by FAS inhibition. Instead,
NADPH accumulation resulting from FAS inhibition was found to stimulate NADPH
oxidase to generate reactive oxygen species and highly associated with apoptosis
induction. Suppression of NADPH oxidase almost totally blocked reactive oxygen
species generation while significantly potentiated the in vitro and in vivo
killing of breast cancers by FAS inhibition. Taken together, these data suggest
that FAS plays a critical role in maintaining cellular redox homeostasis and its
inhibition leads to NADPH accumulation-mediated apoptosis. Our finding may
provide new insights into cancer metabolism and aid in designing effective
anticancer treatments.