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2015 ; 36
(1
): 204-14
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English Wikipedia
Metformin exerts anticancer effects through the inhibition of the Sonic hedgehog
signaling pathway in breast cancer
#MMPMID25999130
Fan C
; Wang Y
; Liu Z
; Sun Y
; Wang X
; Wei G
; Wei J
Int J Mol Med
2015[Jul]; 36
(1
): 204-14
PMID25999130
show ga
Metformin, a widely prescribed antidiabetic drug, has previously been shown to
lower the risk of certain types of cancer, including that of breast cancer, and
to improve prognosis. Its anticancer effects, which are mediated by the
activation of AMP-activated protein kinase (AMPK), have become notable. The Sonic
hedgehog (Shh) signaling pathway is involved in changes in mammary ducts and
malignant transformation. The aim of the present study was to elucidate the role
of the Shh pathway in mediating the anticancer effects of metformin and the
correlation between AMPK and the Shh pathway. We investigated the effectiveness
of metformin in inhibiting the proliferation, migration, invasion and stemness of
breast cancer cells in vitro using RNA extraction and reverse
transcription?polymerase chain reaction (RT-PCR), western blot analysis, cell
proliferation assay, scratch-wound assay (cell migration assay), cell invasion
assay, mammosphere culture and flow cytometry. In in vivo experiments, a tumor
xenograft model was used to detect the effects of metformin on cancer cell
proliferation. The results revealed that the treatment of breast cancer cells
with metformin led to the inhibition of the Shh signaling pathway. Importantly,
metformin inhibited recombinant human Shh (rhShh)?induced cell migration,
invasion, and stemness, and impaired cell proliferation both in vitro and in
vivo. Furthermore, the small interfering RNA (siRNA)?mediated downregulation of
AMPK reversed the inhibitory effects of metformin on rhShh?induced Gli-1
expression and stemness. Our findings identified a role of the Shh signaling
pathway in the anticancer effects of metformin in breast cancer. Furthermore, we
revealed that the metformin-mediated inhibition of the Shh signaling pathway may
be dependent on AMPK.