Polyphyllin I induces mitophagic and apoptotic cell death in human breast cancer cells by increasing mitochondrial PINK1 levels

Li, Guobing�; Fu, Ruoqiu; Shen, Han‐Ming; Zhou, Jing; Hu, Xiaoye; Liu, Yanxia; Li, Yunong; Zhang, Hongwei; Liu, Xin; Zhang, Yanhao; Huang, Cheng; Zhang, Rong; Gao, Ning

doi:10.18632/oncotarget.14413

Cited by 62 publications

(45 citation statements)

References 47 publications

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“…Our transmission electron microscope and confocal microscope assay indicated that IR‐783 increased mitochondrial fragmentation. Researchers have previously demonstrated that Drp1 effectively influences the mitochondrial fission process in cells by translocation of Drp1 to the mitochondrial outer membrane . To further confirm these results in our experiment, western blot analysis showed that treatment of cells with IR‐783 significantly increased the levels of Drp1 in mitochondria in a dose‐dependent manner, decreased the expression of mitochondria fusion regulators Mfn1 and OPA1, and increased the expression of mitochondria fission regulators MFF and Fis1 in the whole cell lysate (Figure D).…”

Section: Resultssupporting

confidence: 85%

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Tang

Liu

Zhang

et al. 2018

J Cellular Molecular Medi

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IR‐783 is a kind of heptamethine cyanine dye that exhibits imaging, cancer targeting and anticancer properties. A previous study reported that its imaging and targeting properties were related to mitochondria. However, the molecular mechanism behind the anticancer activity of IR‐783 has not been well demonstrated. In this study, we showed that IR‐783 inhibits cell viability and induces mitochondrial apoptosis in human breast cancer cells. Exposure of MDA‐MB‐231 cells to IR‐783 resulted in the loss of mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) depletion, mitochondrial permeability transition pore (mPTP) opening and cytochrome c (Cyto C) release. Furthermore, we found that IR‐783 induced dynamin‐related protein 1 (Drp1) translocation from the cytosol to the mitochondria, increased the expression of mitochondrial fission proteins mitochondrial fission factor (MFF) and fission‐1 (Fis1), and decreased the expression of mitochondrial fusion proteins mitofusin1 (Mfn1) and optic atrophy 1 (OPA1). Moreover, knockdown of Drp1 markedly blocked IR‐783‐mediated mitochondrial fission, loss of MMP, ATP depletion, mPTP opening and apoptosis. Our in vivo study confirmed that IR‐783 markedly inhibited tumour growth and induced apoptosis in an MDA‐MB‐231 xenograft model in association with the mitochondrial translocation of Drp1. Taken together, these findings suggest that IR‐783 induces apoptosis in human breast cancer cells by increasing Drp1‐mediated mitochondrial fission. Our study uncovered the molecular mechanism of the anti‐breast cancer effects of IR‐783 and provided novel perspectives for the application of IR‐783 in the treatment of breast cancer.

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Section: Resultssupporting

confidence: 85%

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Tang

Liu

Zhang

et al. 2018

J Cellular Molecular Medi

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“…Increasing evidences has shown that natural products not only serve key roles in the detection and evolvement of novel drugs, but they may be used as molecular probes for screening treatment targets (14,15). Paris polyphyllin is a Polyphyllin I inhibits invasion and epithelial-mesenchymal transition via CIP2A/PP2A/ERK signaling in prostate cancer medicinal herb in the Shennongjia National Nature Reserve of China, which may treat fevers, headaches, burns, wounds, and exhibit immune-regulatory and antitumor abilities (16,17). Polyphyllin I (PPI), a bioactive phytochemical isolated from the rhizoma of P. polyphylla, exhibits preclinical antitumor efficacy in several cancer types, including breast, lung, gastric, and ovarian cancer, as well as osteosarcoma (16,18,19).…”

Section: Introductionmentioning

confidence: 99%

“…Paris polyphyllin is a Polyphyllin I inhibits invasion and epithelial-mesenchymal transition via CIP2A/PP2A/ERK signaling in prostate cancer medicinal herb in the Shennongjia National Nature Reserve of China, which may treat fevers, headaches, burns, wounds, and exhibit immune-regulatory and antitumor abilities (16,17). Polyphyllin I (PPI), a bioactive phytochemical isolated from the rhizoma of P. polyphylla, exhibits preclinical antitumor efficacy in several cancer types, including breast, lung, gastric, and ovarian cancer, as well as osteosarcoma (16,18,19). Recently, PPI was found to increase the sensitivity of liver cancer HepG2 cells to cisplatin, and activate autophagy via the PI3K/Akt/mTOR signaling pathway (20).…”

Section: Introductionmentioning

confidence: 99%

Polyphyllin I inhibits invasion and epithelial-mesenchymal transition via CIP2A/PP2A/ERK signaling in prostate cancer

Sun

Deng

et al. 2018

Int J Oncol

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Polyphyllin I (PPI) is a natural compound extracted from the rhizomes of Paris polyphylla and has been used to treat fevers and headaches in China. In the present study, the antitumor activity of PPI in prostate cancer (PC) cells was evaluated. At low doses, PPI decreased proliferation, invasion and epithelial-mesenchymal transition (EMT) in PC cells. PPI decreased the expression of matrix metalloproteinase 7 (MMP7), an enzyme that is critical for tumor metastasis. PPI also decreased the expression of Snail and vimentin, which are EMT-associated factors. Additionally, PPI suppressed AP-1 transcriptional activity and AP-1 binding to the MMP7 and vimentin promoters. The results demonstrated that PPI downregulated the phosphorylation of extracellular signaling‑related kinase (ERK), which is upstream modulator of AP-1. The results of the present study demonstrated that PPI may inhibit the cancerous inhibitor of protein phosphatase 2A (CIP2A)/protein phosphatase 2A (PP2A)/ERK axis, downregulate the expression of MMP7, vimentin, and Snail, and suppress tumor invasion and EMT. A PC xenograft mouse model was employed and the results revealed that PPI may decrease tumor growth and weight. Additionally, PPI may inhibit proliferating cell nuclear antigen expression and CIP2A/PP2A/ERK signaling pathway in PPI-treated tumors. Therefore, the results of the present study suggest that PPI may suppress the growth, invasion and EMT of PC cells via inhibition of CIP2A/PP2A/ERK signaling axis. As a result, PPI may be a novel target for the treatment of PC.

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“…In one study, PPI inhibited tumor growth and induced apoptosis in human breast cancer cells, and these effects were enhanced by activating the PTEN-induced kinase 1 signaling pathway [11]. PPI also demonstrated anti-tumor activity on ovarian cancer in vivo via modulation of caspase-9, c-Jun, and secreted glycoprotein Wnt5a [13].…”

Section: Introductionmentioning

confidence: 99%

Crosstalk of NF-κB/P65 and LncRNA HOTAIR-Mediated Repression of MUC1 Expression Contribute to Synergistic Inhibition of Castration-Resistant Prostate Cancer by Polyphyllin 1–Enzalutamide Combination Treatment

Xiang

Zou

et al. 2018

Cell Physiol Biochem

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Background/Aims: Polyphyllin I (PPI), one of the steroidal saponins in Paris polyphylla, reportedly exhibits antitumor effects. However, the detailed mechanism underlying PPI, particularly in enhancing the effect of the androgen receptor inhibitor enzalutamide in controlling castration-resistant prostate cancer (CRPC) has not been explored. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) expression was measured by quantitative real time-PCR (qRT-PCR). Western blot analysis was performed to determine the protein expression levels of MUC1, p65, and p50. Silencing of HOTAIR was evaluated using the siRNA procedure. The promoter activity of the MUC1 gene was determined using Secrete-Pair Dual Luminescence Assay Kit. Exogenous expression of HOTAIR, p65, and MUC1 was conducted by transient transfection assay. A xenograft tumor model in nude mice was used to further evaluate the effect of the combination of PPI and enzalutamide in vivo. Results: We showed that PPI significantly inhibited growth and induced cell cycle arrest in CRPC cells. PPI also decreased p65 and MUC1 protein expression and reduced HOTAIR expression. Exogenously expressed p65 resisted the PPI-inhibited expression of HOTAIR, whereas silenced HOTAIR reduced MUC1 protein but exerted no effect on the expression of p65 and p50 proteins. Conversely, exogenously expressed HOTAIR resisted the PPI-inhibited MUC1 protein expression, and excessive expression of MUC1 antagonized the PPI-inhibited cell growth. Notably, PPI combined with enzalutamide exerted a synergistic effect. Consistent with this finding, PPI inhibited tumor growth, HOTAIR expression, as well as p65 and MUC1 protein expressions in vivo. Conclusions: Our results indicate that PPI inhibits the growth of CRPC cells by inhibiting p65 protein and concomitantly reducing HOTAIR expression, thereby suppressing MUC1 gene expression. The novel regulatory interaction of p65 and HOTAIR converge in the inhibition of MUC1 expression and overall PPI response. The combination of PPI and enzalutamide exhibits synergy. This study reveals a novel mechanism underlying the synergistic inhibitory effect of PPI and enzalutamide on the growth of CRPC cells.

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Polyphyllin I induces mitophagic and apoptotic cell death in human breast cancer cells by increasing mitochondrial PINK1 levels

Cited by 62 publications

References 47 publications

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Polyphyllin I inhibits invasion and epithelial-mesenchymal transition via CIP2A/PP2A/ERK signaling in prostate cancer

Crosstalk of NF-κB/P65 and LncRNA HOTAIR-Mediated Repression of MUC1 Expression Contribute to Synergistic Inhibition of Castration-Resistant Prostate Cancer by Polyphyllin 1–Enzalutamide Combination Treatment

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