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2016 ; 18
(1
): 38
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Naringenin prevents TGF-?1 secretion from breast cancer and suppresses pulmonary
metastasis by inhibiting PKC activation
#MMPMID27036297
Zhang F
; Dong W
; Zeng W
; Zhang L
; Zhang C
; Qiu Y
; Wang L
; Yin X
; Zhang C
; Liang W
Breast Cancer Res
2016[Apr]; 18
(1
): 38
PMID27036297
show ga
BACKGROUND: Targeting the TGF-?1 pathway for breast cancer metastasis therapy has
become an attractive strategy. We have previously demonstrated that naringenin
significantly reduced TGF-?1 levels in bleomycin-induced lung fibrosis and
effectively prevented pulmonary metastases of tumors. This raised the question of
whether naringenin can block TGF-?1 secretion from breast cancer cells and
inhibit their pulmonary metastasis. METHODS: We transduced a lentiviral vector
encoding the mouse Tgf-?1 gene into mouse breast carcinoma (4T1-Luc2) cells and
inoculated the transformant cells (4T1/TGF-?1) into the fourth primary fat pat of
Balb/c mice. Pulmonary metastases derived from the primary tumors were monitored
using bioluminescent imaging. Spleens, lungs and serum (n?=?18-20 per treatment
group) were analyzed for immune cell activity and TGF-?1 level. The mechanism
whereby naringenin decreases TGF-?1 secretion from breast cancer cells was
investigated at different levels, including Tgf-?1 transcription, mRNA stability,
translation, and extracellular release. RESULTS: In contrast to the null-vector
control (4T1/RFP) tumors, extensive pulmonary metastases derived from 4T1/TGF-?1
tumors were observed. Administration of the TGF-?1 blocking antibody 1D11 or
naringenin showed an inhibition of pulmonary metastasis for both 4T1/TGF-?1
tumors and 4T1/RFP tumors, resulting in increased survival of the mice. Compared
with 4T1/RFP bearing mice, systemic immunosuppression in 4T1/TGF-?1 bearing mice
was observed, represented by a higher proportion of regulatory T cells and
myeloid-derived suppressor cells and a lower proportion of activated T cells and
INF? expression in CD8(+) T cells. These metrics were improved by administration
of 1D11 or naringenin. However, compared with 1D11, which neutralized secreted
TGF-?1 but did not affect intracellular TGF-?1 levels, naringenin reduced the
secretion of TGF-?1 from the cells, leading to an accumulation of intracellular
TGF-?1. Further experiments revealed that naringenin had no effect on Tgf-?1
transcription, mRNA decay or protein translation, but prevented TGF-?1 transport
from the trans-Golgi network by inhibiting PKC activity. CONCLUSIONS: Naringenin
blocks TGF-?1 trafficking from the trans-Golgi network by suppressing PKC
activity, resulting in a reduction of TGF-?1 secretion from breast cancer cells.
This finding suggests that naringenin may be an attractive therapeutic candidate
for TGF-?1 related diseases.
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