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. 2018 Oct 15;9(11):1050.
doi: 10.1038/s41419-018-1083-y.

Positive feedback loop between mitochondrial fission and Notch signaling promotes survivin-mediated survival of TNBC cells

Li Chen  1 , Jing Zhang  1 , Zhuomin Lyu  2 , Yibing Chen  3 , Xiaoying Ji  1 , Haiyan Cao  1 , Mingpeng Jin  1 , Jianjun Zhu  1 , Jin Yang  4 , Rui Ling  5 , Jinliang Xing  1 , Tingting Ren  6 , Yonggang Lyu  7   8
Affiliations

Positive feedback loop between mitochondrial fission and Notch signaling promotes survivin-mediated survival of TNBC cells

Li Chen et al. Cell Death Dis. .

Abstract

Mitochondrial morphology is remodeled by continuous dynamic cycles of fission and fusion. Emerging data have shown that the disturbance of balance between mitochondrial fission and fusion is involved in the progression of several types of neoplasms. However, the status of mitochondrial dynamics and its potential biological roles in breast cancer (BC), particularly in triple negative BC (TNBC) are not fully clear. Here, we reported that the mitochondrial fission was significantly increased in BC tissues, especially in the TNBC tissues, when compared with that in the corresponding peritumor tissues. Meanwhile, our data showed that Drp1 was upregulated, while Mfn1 was downregulated in TNBC. Moreover, elevated mitochondrial fission was associated with poorer prognosis in TNBC patients. Mitochondrial fission promoted the survival of TNBC cells both in vitro and in vivo. Furthermore, we identified a positive feedback loop between mitochondrial fission and Notch signaling pathway in TNBC cells, as proved by the experimental evidence that the activation of Notch signaling enhanced Drp1-mediated mitochondrial fission and Drp1-mediated mitochondrial fission in turn promoted the activation of Notch signaling, which ultimately promoted the cell survival of TNBC via increasing survivin expression level. Inhibition of either Notch1 or Drp1 significantly impaired the activation of the other, leading to the suppression of TNBC cell survival and proliferation. Collectively, our data reveal a novel mechanism that the positive feedback loop between mitochondrial fission and Notch signaling promotes the survival, proliferation and apoptotic resistance of TNBC cells via increasing survivin expression and thus favors cancer progression.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Fig. 1
Fig. 1. Mitochondrial fission was increased in TNBC and contributes to poor patient prognosis.
a TEM images of mitochondrial network in paired tissues from TNBC patients (n = 12) and non-TNBC patients (n = 15). N, nucleus. Scale bar: 0.5 μm. b IHC staining images of Drp1 and Mfn1 in paired TNBC tissues (n = 62) and non-TNBC tissues (n = 93). Scale bar: 100 μm. *P < 0.05; **P < 0.01. c The relative mRNA expression ratio (Log2 transformed) of tumor/peritumor for Drp1 and Mfn1 measured by qRT-PCR in 155 pairs of BC tissues. d Western blot for expression levels of Drp1 and Mfn1 in human breast cell lines. e Kaplan–Meier curve of overall survival in TNBC patients with different expression levels of Drp1 and Mfn1. f The protein expression levels of Drp1 and Mfn1 in tissue chips of stage II/III TNBC patients (n = 62) were evaluated based on score of IHC staining
Fig. 2
Fig. 2. Mitochondrial dynamics was remodeled by regulating Drp1 and Mfn1 in TNBC cells.
After TNBC cells (MDA-MB-231 and MDA-MB-468) were transfected with expression vectors or siRNA for 48 h, MitoTracker green staining and confocal microscopy analysis of mitochondrial network were performed as described EV, Drp1, Mfn1, siCtrl, siDrp1, siMfn1. Scale bars: 5 μm. *P < 0.05; **P < 0.01
Fig. 3
Fig. 3. Mitochondrial fission promoted cell survival in TNBC cells.
a, b MTS cell viability was analyzed in TNBC cells treated as indicated. c, d Tumor growth curves of subcutaneous xenograft tumor model and dissected tumors from sacrificed mice
Fig. 4
Fig. 4. Mitochondrial fission inhibited TNBC cell apoptosis.
a–d Apoptosis of TNBC cells analyzed by flow cytometry 48 h after siRNAs or plasmid transfection. Apoptosis was induced by 1 μM thapsigargin for 24 h. e, f TUNEL staining in tumor tissues dissected from xenograft tumors developed from MDA-MB-231 cells with different mitochondrial dynamic status. Green, TUNEL-positive nucleus; Blue, Hochest33342. Scale bar: 50 μm. *P < 0.05; **P < 0.01
Fig. 5
Fig. 5. Mitochondrial fission promoted TNBC cell proliferation.
a–d Proliferation of TNBC cells evaluated by EdU incorporation analysis after different treatment. Data was presented as mean ± SEM, n = 3. *P < 0.05; **P < 0.01. e, f Representative IHC staining images of Ki67 in tumor tissues dissected from xenograft tumor treated as indicated. Scale bar: 50 μm. *P < 0.05; **P < 0.01
Fig. 6
Fig. 6. A positive feedback loop between mitochondrial fission and notch signaling.
a–c Western blot analysis for Drp1, Mfn1, Notch1 and NICD1 in TNBC cells with different treatment. d Changes of mitochondrial dynamics in TNBC cells after Notch signaling alterations. Scale bar: 5 μm. *P < 0.05; **P < 0.01. e Correlation between IHC scores of Notch1 and Drp1 or Mfn1 in 124 TNBC tissues
Fig. 7
Fig. 7. Notch-mitochondrial fission positive feedback loop regulated cell apoptosis and proliferation in TNBC.
a, b Thapsigargin-induced apoptosis analyzed by flow cytometry in TNBC cells after transfection with different siRNAs or plasmids. c, d Cell proliferation determined by EdU analysis in TNBC cells 48 h after transfection with different expression vectors or siRNAs. Data was presented as mean ± SEM, n = 3. *P < 0.05; **P < 0.01
Fig. 8
Fig. 8. Notch-mitochondrial fission positive feedback loop-induced survivin expression promoted TNBC cell survival.
a–d Western blot analysis for Drp1, Notch1, NICD1 and survivin in TNBC cells with transfection as indicated. e, f Cell viability analyzed by MTS in TNBC cells transfected with expression vectors or siRNAs as indicated. *P < 0.05; **P < 0.01. g Schematic depicting the effect of the feedback loop between mitochondrial dynamics and Notch signaling on TNBC cell survival and underlying mechanism
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