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Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

Delphinidin induced protective autophagy via mTOR pathway suppression and AMPK pathway activation in HER-2 positive breast cancer cells

Authors: Jingyao Chen, Yanfeng Zhu, Weiwei Zhang, Xiaoli Peng, Jie Zhou, Fei Li, Bin Han, Xin Liu, Yu Ou, Xiaoping Yu

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

We have previously demonstrated the anticancer effect of anthocyanins. In this study, we explored the biological activities of delphinidin, the most common of the anthocyanidin monomers, that were related to autophagy in HER-2 positive breast cancer MDA-MB-453 and BT474 cells.

Methods

The effects of various doses of delphinidin on the proliferation and apoptosis of MDA-MB-453 and BT474 cells were analysed. Autophagy was identified as a critical factor that influenced chemotherapy, and the autophagic mechanism in delphinidin-treated cells was investigated. The autophagy inhibitors, 3-MA and BA1, were used to analyse the effects of autophagy inhibition.

Results

Delphinidin inhibited proliferation, promoted apoptosis, and induced autophagy in MDA-MB-453 and BT474 cells in a dose-dependent manner. The inhibition of autophagy enhanced the delphinidin-induced apoptosis and antiproliferative effect in both HER-2 positive breast cancer cells. In addition, delphinidin induced autophagy via suppression of the mTOR signalling pathway and activation of the AMPK signalling pathway in HER-2 positive breast cancer cells.

Conclusions

Collectively, the results showed that delphinidin induced apoptosis and autophagy in HER-2 positive breast cancer cells and that autophagy was induced via the mTOR and AMPK signalling pathways. The suppression of autophagy promoted the anticancer effects of delphinidin.
Literature
2.
go back to reference Fabi A, Malaguti P, Vari S, Cognetti F. First-line therapy in HER2 positive metastatic breast cancer: is the mosaic fully completed or are we missing additional pieces? J Exp Clin Cancer Res. 2016;35:104.CrossRefPubMedPubMedCentral Fabi A, Malaguti P, Vari S, Cognetti F. First-line therapy in HER2 positive metastatic breast cancer: is the mosaic fully completed or are we missing additional pieces? J Exp Clin Cancer Res. 2016;35:104.CrossRefPubMedPubMedCentral
3.
go back to reference Jing P, Qian B, Zhao S, Qi X, Ye L, Monica Giusti M, et al. Effect of glycosylation patterns of Chinese eggplant anthocyanins and other derivatives on antioxidant effectiveness in human colon cell lines. Food Chem. 2015;172:183–9.CrossRefPubMed Jing P, Qian B, Zhao S, Qi X, Ye L, Monica Giusti M, et al. Effect of glycosylation patterns of Chinese eggplant anthocyanins and other derivatives on antioxidant effectiveness in human colon cell lines. Food Chem. 2015;172:183–9.CrossRefPubMed
4.
go back to reference Chen XY, Zhou J, Luo LP, Han B, Li F, Chen JY, et al. Black Rice Anthocyanins Suppress Metastasis of Breast Cancer Cells by Targeting RAS/RAF/MAPK Pathway. Biomed Res Int. 2015;2015:414250.PubMedPubMedCentral Chen XY, Zhou J, Luo LP, Han B, Li F, Chen JY, et al. Black Rice Anthocyanins Suppress Metastasis of Breast Cancer Cells by Targeting RAS/RAF/MAPK Pathway. Biomed Res Int. 2015;2015:414250.PubMedPubMedCentral
5.
go back to reference Luo LP, Han B, Yu XP, Chen XY, Zhou J, Chen W, et al. Anti-metastasis activity of black rice anthocyanins against breast cancer: analyses using an ErbB2 positive breast cancer cell line and tumoral xenograft model. Asian Pac J Cancer Prev. 2014;15:6219–25.CrossRefPubMed Luo LP, Han B, Yu XP, Chen XY, Zhou J, Chen W, et al. Anti-metastasis activity of black rice anthocyanins against breast cancer: analyses using an ErbB2 positive breast cancer cell line and tumoral xenograft model. Asian Pac J Cancer Prev. 2014;15:6219–25.CrossRefPubMed
6.
go back to reference Yang X, Luo E, Liu X, Han B, Yu X, Peng X. Delphinidin-3-glucoside suppresses breast carcinogenesis by inactivating the Akt/HOTAIR signaling pathway. BMC Cancer. 2016;16:423.CrossRefPubMedPubMedCentral Yang X, Luo E, Liu X, Han B, Yu X, Peng X. Delphinidin-3-glucoside suppresses breast carcinogenesis by inactivating the Akt/HOTAIR signaling pathway. BMC Cancer. 2016;16:423.CrossRefPubMedPubMedCentral
7.
go back to reference Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, et al. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis. 2013;4:e838.CrossRefPubMedPubMedCentral Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, et al. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis. 2013;4:e838.CrossRefPubMedPubMedCentral
8.
go back to reference Moon JY, Cho SK. Nobiletin Induces Protective Autophagy Accompanied by ER-Stress Mediated Apoptosis in Human Gastric Cancer SNU-16 Cells. Molecules. 2016;21:914.CrossRef Moon JY, Cho SK. Nobiletin Induces Protective Autophagy Accompanied by ER-Stress Mediated Apoptosis in Human Gastric Cancer SNU-16 Cells. Molecules. 2016;21:914.CrossRef
9.
go back to reference Ye H, Chen M, Cao F, Huang H, Zhan R, Zheng X. Chloroquine, an autophagy inhibitor, potentiates the radiosensitivity of glioma initiating cells by inhibiting autophagy and activating apoptosis. BMC Neurol. 2016;16:178.CrossRefPubMedPubMedCentral Ye H, Chen M, Cao F, Huang H, Zhan R, Zheng X. Chloroquine, an autophagy inhibitor, potentiates the radiosensitivity of glioma initiating cells by inhibiting autophagy and activating apoptosis. BMC Neurol. 2016;16:178.CrossRefPubMedPubMedCentral
10.
go back to reference Law BY, Mok SW, Chan WK, Xu SW, Wu AG, Yao XJ, et al. Hernandezine, a novel AMPK activator induces autophagic cell death in drug-resistant cancers. Oncotarget. 2016;7:8090–104.CrossRefPubMedPubMedCentral Law BY, Mok SW, Chan WK, Xu SW, Wu AG, Yao XJ, et al. Hernandezine, a novel AMPK activator induces autophagic cell death in drug-resistant cancers. Oncotarget. 2016;7:8090–104.CrossRefPubMedPubMedCentral
11.
go back to reference Wu T, Wang MC, Jing L, Liu ZY, Guo H, Liu Y, et al. Autophagy facilitates lung adenocarcinoma resistance to cisplatin treatment by activation of AMPK/mTOR signaling pathway. Drug Des Devel Ther. 2015;9:6421–31.CrossRefPubMedPubMedCentral Wu T, Wang MC, Jing L, Liu ZY, Guo H, Liu Y, et al. Autophagy facilitates lung adenocarcinoma resistance to cisplatin treatment by activation of AMPK/mTOR signaling pathway. Drug Des Devel Ther. 2015;9:6421–31.CrossRefPubMedPubMedCentral
12.
go back to reference Wang KF, Yang H, Jiang WQ, Li S, Cai YC. Puquitinib mesylate (XC-302) induces autophagy via inhibiting the PI3K/AKT/mTOR signaling pathway in nasopharyngeal cancer cells. Int J Mol Med. 2015;36:1556–62.CrossRefPubMedPubMedCentral Wang KF, Yang H, Jiang WQ, Li S, Cai YC. Puquitinib mesylate (XC-302) induces autophagy via inhibiting the PI3K/AKT/mTOR signaling pathway in nasopharyngeal cancer cells. Int J Mol Med. 2015;36:1556–62.CrossRefPubMedPubMedCentral
13.
go back to reference Lepine S, Allegood JC, Edmonds Y, Milstien S, Spiegel S. Autophagy induced by deficiency of sphingosine-1-phosphate phosphohydrolase 1 is switched to apoptosis by calpainmediated autophagy-related gene 5 (Atg5) cleavage. J Biol Chem. 2011;286:44380–90.CrossRefPubMedPubMedCentral Lepine S, Allegood JC, Edmonds Y, Milstien S, Spiegel S. Autophagy induced by deficiency of sphingosine-1-phosphate phosphohydrolase 1 is switched to apoptosis by calpainmediated autophagy-related gene 5 (Atg5) cleavage. J Biol Chem. 2011;286:44380–90.CrossRefPubMedPubMedCentral
14.
go back to reference Shi JM, Bai LL, Zhang DM, Yiu A, Yin ZQ, Han WL, et al. Saxifragifolin D induces the interplay between apoptosis and autophagy in breast cancer cells through ROS-dependent endoplasmic reticulum stress. Biochem Pharmacol. 2013;85:913–26.CrossRefPubMed Shi JM, Bai LL, Zhang DM, Yiu A, Yin ZQ, Han WL, et al. Saxifragifolin D induces the interplay between apoptosis and autophagy in breast cancer cells through ROS-dependent endoplasmic reticulum stress. Biochem Pharmacol. 2013;85:913–26.CrossRefPubMed
15.
go back to reference Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 2000;19:5720–8.CrossRefPubMedPubMedCentral Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 2000;19:5720–8.CrossRefPubMedPubMedCentral
16.
go back to reference Das G, Shravage BV, Baehrecke EH. Regulation and function of autophagy during cell survival and cell death. Cold Spring Harb Perspect Biol 2012;4. Das G, Shravage BV, Baehrecke EH. Regulation and function of autophagy during cell survival and cell death. Cold Spring Harb Perspect Biol 2012;4.
17.
go back to reference Kim SH, Choi YJ, Kim KY, Yu SN, Seo YK, Chun SS, et al. Salinomycin simultaneously induces apoptosis and autophagy through generation of reactive oxygen species in osteosarcoma U2OS cells. Biochem Biophys Res Commun. 2016;473:607–13.CrossRefPubMed Kim SH, Choi YJ, Kim KY, Yu SN, Seo YK, Chun SS, et al. Salinomycin simultaneously induces apoptosis and autophagy through generation of reactive oxygen species in osteosarcoma U2OS cells. Biochem Biophys Res Commun. 2016;473:607–13.CrossRefPubMed
18.
go back to reference Vegliante R, Desideri E, Di Leo L, Ciriolo MR. Dehydroepiandrosterone triggers autophagic cell death in human hepatoma cell line HepG2 via JNK-mediated p62/SQSTM1 expression. Carcinogenesis. 2016;37:233–44.CrossRefPubMed Vegliante R, Desideri E, Di Leo L, Ciriolo MR. Dehydroepiandrosterone triggers autophagic cell death in human hepatoma cell line HepG2 via JNK-mediated p62/SQSTM1 expression. Carcinogenesis. 2016;37:233–44.CrossRefPubMed
19.
go back to reference Chen H, Duo Y, Hu B, Wang Z, Zhang F, Tsai H, et al. PICT-1 triggers a pro-death autophagy through inhibiting rRNA transcription and AKT/mTOR/p70S6K signaling pathway. Oncotarget. 2016;7:78747–63.PubMedPubMedCentral Chen H, Duo Y, Hu B, Wang Z, Zhang F, Tsai H, et al. PICT-1 triggers a pro-death autophagy through inhibiting rRNA transcription and AKT/mTOR/p70S6K signaling pathway. Oncotarget. 2016;7:78747–63.PubMedPubMedCentral
20.
go back to reference Li Y, Liu Y, Shi F, Cheng L, She J. Knockdown of Rap1b Enhances Apoptosis and Autophagy in Gastric Cancer Cells via the PI3K/Akt/mTOR Pathway. Oncol Res. 2016;24:287–93.CrossRefPubMed Li Y, Liu Y, Shi F, Cheng L, She J. Knockdown of Rap1b Enhances Apoptosis and Autophagy in Gastric Cancer Cells via the PI3K/Akt/mTOR Pathway. Oncol Res. 2016;24:287–93.CrossRefPubMed
21.
go back to reference Wang K, Liu R, Li J, Mao J, Lei Y, Wu J, et al. Quercetin induces protective autophagy in gastric cancer cells: involvement of Akt-mTOR- and hypoxia-induced factor 1alpha-mediated signaling. Autophagy. 2011;7:966–78.CrossRefPubMed Wang K, Liu R, Li J, Mao J, Lei Y, Wu J, et al. Quercetin induces protective autophagy in gastric cancer cells: involvement of Akt-mTOR- and hypoxia-induced factor 1alpha-mediated signaling. Autophagy. 2011;7:966–78.CrossRefPubMed
22.
go back to reference Coffey RT, Shi Y, Long MJ, Marr MT 2nd, Hedstrom L. Ubiquilin-mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling. J Biol Chem. 2016;291:5221–33.CrossRefPubMedPubMedCentral Coffey RT, Shi Y, Long MJ, Marr MT 2nd, Hedstrom L. Ubiquilin-mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling. J Biol Chem. 2016;291:5221–33.CrossRefPubMedPubMedCentral
23.
go back to reference Shang L, Chen S, Du F, Li S, Zhao L, Wang X. Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proc Natl Acad Sci U S A. 2011;108:4788–93.CrossRefPubMedPubMedCentral Shang L, Chen S, Du F, Li S, Zhao L, Wang X. Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proc Natl Acad Sci U S A. 2011;108:4788–93.CrossRefPubMedPubMedCentral
24.
go back to reference Aryal P, Kim K, Park PH, Ham S, Cho J, Song K. Baicalein induces autophagic cell death through AMPK/ULK1 activation and downregulation of mTORC1 complex components in human cancer cells. FEBS J. 2014;281:4644–58.CrossRefPubMed Aryal P, Kim K, Park PH, Ham S, Cho J, Song K. Baicalein induces autophagic cell death through AMPK/ULK1 activation and downregulation of mTORC1 complex components in human cancer cells. FEBS J. 2014;281:4644–58.CrossRefPubMed
25.
go back to reference Kim JH, Lee JO, Kim N, Lee HJ, Lee YW, Kim HI, et al. Paclitaxel suppresses the viability of breast tumor MCF7 cells through the regulation of EF1alpha and FOXO3a by AMPK signaling. Int J Oncol. 2015;47:1874–80.CrossRefPubMed Kim JH, Lee JO, Kim N, Lee HJ, Lee YW, Kim HI, et al. Paclitaxel suppresses the viability of breast tumor MCF7 cells through the regulation of EF1alpha and FOXO3a by AMPK signaling. Int J Oncol. 2015;47:1874–80.CrossRefPubMed
26.
go back to reference Lim W, Jeong W, Song G. Delphinidin suppresses proliferation and migration of human ovarian clear cell carcinoma cells through blocking AKT and ERK1/2 MAPK signaling pathways. Mol Cell Endocrinol. 2016;422:172–81.CrossRefPubMed Lim W, Jeong W, Song G. Delphinidin suppresses proliferation and migration of human ovarian clear cell carcinoma cells through blocking AKT and ERK1/2 MAPK signaling pathways. Mol Cell Endocrinol. 2016;422:172–81.CrossRefPubMed
27.
go back to reference Chakrabarti M, Ray SK. Direct transfection of miR-137 mimics is more effective than DNA demethylation of miR-137 promoter to augment anti-tumor mechanisms of delphinidin in human glioblastoma U87MG and LN18 cells. Gene. 2015;573:141–52.CrossRefPubMed Chakrabarti M, Ray SK. Direct transfection of miR-137 mimics is more effective than DNA demethylation of miR-137 promoter to augment anti-tumor mechanisms of delphinidin in human glioblastoma U87MG and LN18 cells. Gene. 2015;573:141–52.CrossRefPubMed
28.
go back to reference Zhou Y, Liang X, Chang H, Shu F, Wu Y, Zhang T, et al. Ampelopsin-induced autophagy protects breast cancer cells from apoptosis through Akt-mTOR pathway via endoplasmic reticulum stress. Cancer Sci. 2014;105:1279–87.CrossRefPubMedPubMedCentral Zhou Y, Liang X, Chang H, Shu F, Wu Y, Zhang T, et al. Ampelopsin-induced autophagy protects breast cancer cells from apoptosis through Akt-mTOR pathway via endoplasmic reticulum stress. Cancer Sci. 2014;105:1279–87.CrossRefPubMedPubMedCentral
29.
go back to reference Wang YF, Li T, Tang ZH, Chang LL, Zhu H, Chen XP, et al. Baicalein Triggers Autophagy and Inhibits the Protein Kinase B/Mammalian Target of Rapamycin Pathway in Hepatocellular Carcinoma HepG2 Cells. Phytother Res. 2015;29:674–9.CrossRefPubMed Wang YF, Li T, Tang ZH, Chang LL, Zhu H, Chen XP, et al. Baicalein Triggers Autophagy and Inhibits the Protein Kinase B/Mammalian Target of Rapamycin Pathway in Hepatocellular Carcinoma HepG2 Cells. Phytother Res. 2015;29:674–9.CrossRefPubMed
30.
go back to reference Lu J, Sun D, Gao S, Gao Y, Ye J, Liu P. Cyclovirobuxine D induces autophagy-associated cell death via the Akt/mTOR pathway in MCF-7 human breast cancer cells. J Pharmacol Sci. 2014;125:74–82.CrossRefPubMed Lu J, Sun D, Gao S, Gao Y, Ye J, Liu P. Cyclovirobuxine D induces autophagy-associated cell death via the Akt/mTOR pathway in MCF-7 human breast cancer cells. J Pharmacol Sci. 2014;125:74–82.CrossRefPubMed
31.
go back to reference Nozaki R, Kono T, Bochimoto H, Watanabe T, Oketani K, Sakamaki Y, et al. Zanthoxylum fruit extract from Japanese pepper promotes autophagic cell death in cancer cells. Oncotarget. 2016;7:70437–46.CrossRefPubMedPubMedCentral Nozaki R, Kono T, Bochimoto H, Watanabe T, Oketani K, Sakamaki Y, et al. Zanthoxylum fruit extract from Japanese pepper promotes autophagic cell death in cancer cells. Oncotarget. 2016;7:70437–46.CrossRefPubMedPubMedCentral
32.
go back to reference Taylor RC, Cullen SP, Martin SJ. Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol. 2008;9:231–41.CrossRefPubMed Taylor RC, Cullen SP, Martin SJ. Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol. 2008;9:231–41.CrossRefPubMed
33.
go back to reference Estaquier J, Vallette F, Vayssiere JL, Mignotte B. The mitochondrial pathways of apoptosis. Adv Exp Med Biol. 2012;942:157–83.CrossRefPubMed Estaquier J, Vallette F, Vayssiere JL, Mignotte B. The mitochondrial pathways of apoptosis. Adv Exp Med Biol. 2012;942:157–83.CrossRefPubMed
34.
go back to reference Moosavi MA, Sharifi M, Ghafary SM, Mohammadalipour Z, Khataee A, Rahmati M, et al. Photodynamic N-TiO2 Nanoparticle Treatment Induces Controlled ROS-mediated Autophagy and Terminal Differentiation of Leukemia Cells. Sci Rep. 2016;6:34413.CrossRefPubMedPubMedCentral Moosavi MA, Sharifi M, Ghafary SM, Mohammadalipour Z, Khataee A, Rahmati M, et al. Photodynamic N-TiO2 Nanoparticle Treatment Induces Controlled ROS-mediated Autophagy and Terminal Differentiation of Leukemia Cells. Sci Rep. 2016;6:34413.CrossRefPubMedPubMedCentral
35.
go back to reference Li YC, He SM, He ZX, Li M, Yang Y, Pang JX, et al. Plumbagin induces apoptotic and autophagic cell death through inhibition of the PI3K/Akt/mTOR pathway in human nonsmall cell lung cancer cells. Cancer Lett. 2014;344:239–59.CrossRefPubMed Li YC, He SM, He ZX, Li M, Yang Y, Pang JX, et al. Plumbagin induces apoptotic and autophagic cell death through inhibition of the PI3K/Akt/mTOR pathway in human nonsmall cell lung cancer cells. Cancer Lett. 2014;344:239–59.CrossRefPubMed
36.
go back to reference Steelman LS, Martelli AM, Cocco L, Libra M, Nicoletti F, Abrams SL, et al. The therapeutic potential of mTOR inhibitors in breast cancer. Br J Clin Pharmacol. 2016;82:1189–212.CrossRefPubMedPubMedCentral Steelman LS, Martelli AM, Cocco L, Libra M, Nicoletti F, Abrams SL, et al. The therapeutic potential of mTOR inhibitors in breast cancer. Br J Clin Pharmacol. 2016;82:1189–212.CrossRefPubMedPubMedCentral
37.
go back to reference Yao F, Zhang M, Chen L. 5'-Monophosphate-activated protein kinase (AMPK) improves autophagic activity in diabetes and diabetic complications. Acta Pharm Sin B. 2016;6:20–5.CrossRefPubMed Yao F, Zhang M, Chen L. 5'-Monophosphate-activated protein kinase (AMPK) improves autophagic activity in diabetes and diabetic complications. Acta Pharm Sin B. 2016;6:20–5.CrossRefPubMed
39.
go back to reference Chi Y, Shi C, Zhao Y, Guo C. Forkhead box O (FOXO) 3 modulates hypoxia-induced autophagy through AMPK signalling pathway in cardiomyocytes. Biosci Rep. 2016;36 Chi Y, Shi C, Zhao Y, Guo C. Forkhead box O (FOXO) 3 modulates hypoxia-induced autophagy through AMPK signalling pathway in cardiomyocytes. Biosci Rep. 2016;36
40.
go back to reference Nepal S, Park PH. Activation of autophagy by globular adiponectin attenuates ethanol-induced apoptosis in HepG2 cells: involvement of AMPK/FoxO3A axis. Biochim Biophys Acta. 1833;2013:2111–25. Nepal S, Park PH. Activation of autophagy by globular adiponectin attenuates ethanol-induced apoptosis in HepG2 cells: involvement of AMPK/FoxO3A axis. Biochim Biophys Acta. 1833;2013:2111–25.
Metadata
Title
Delphinidin induced protective autophagy via mTOR pathway suppression and AMPK pathway activation in HER-2 positive breast cancer cells
Authors
Jingyao Chen
Yanfeng Zhu
Weiwei Zhang
Xiaoli Peng
Jie Zhou
Fei Li
Bin Han
Xin Liu
Yu Ou
Xiaoping Yu
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4231-y

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