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Erschienen in: Tumor Biology 7/2016

07.01.2016 | Original Article

Neferine induces autophagy of human ovarian cancer cells via p38 MAPK/ JNK activation

verfasst von: Limei Xu, Xiyu Zhang, Yinuo Li, Shuhua Lu, Shan Lu, Jieyin Li, Yuqiong Wang, Xiaoxue Tian, Jian-jun Wei, Changshun Shao, Zhaojian Liu

Erschienen in: Tumor Biology | Ausgabe 7/2016

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Abstract

Ovarian cancer is the most lethal gynecological malignancy. Patients usually have poor prognosis because of late diagnosis, relapse, and chemoresistance. It is pressing to seek novel agent for the treatment of ovarian cancer. Neferine is a bisbenzylisoquinoline alkaloid isolated from the embryos of lotus (Nelumbo nucifera). In this study, we investigated the antitumor effect of neferine on ovarian cancer cells. We found that neferine exhibited growth-inhibitory effect on human ovarian cancer cells, whereas showing less cytotoxic to non-malignant fallopian tube epithelial cells. Furthermore, we demonstrated that neferine induced autophagy and inactivated the mTOR pathway. Finally, we found that both p38 MAPK and JNK signaling pathways were activated by neferine treatment and contributed to the induction of autophagy in ovarian cancer cells. In conclusion, our findings showed that neferine induced autophagy of human ovarian cancer cells via p38 MAPK/JNK activation. Neferine may be explored as a promising antitumoral agent in ovarian cancer.
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Literatur
1.
Zurück zum Zitat Vaughan S, Coward JI, Bast Jr RC, Berchuck A, Berek JS, Brenton JD, et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer. 2011;11:719–25.CrossRefPubMedPubMedCentral Vaughan S, Coward JI, Bast Jr RC, Berchuck A, Berek JS, Brenton JD, et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer. 2011;11:719–25.CrossRefPubMedPubMedCentral
2.
Zurück zum Zitat Gamarra-Luques CD, Hapon MB, Goyeneche AA, Telleria CM. Resistance to cisplatin and paclitaxel does not affect the sensitivity of human ovarian cancer cells to antiprogestin-induced cytotoxicity. J Ovarian Res. 2014;7:45.CrossRefPubMedPubMedCentral Gamarra-Luques CD, Hapon MB, Goyeneche AA, Telleria CM. Resistance to cisplatin and paclitaxel does not affect the sensitivity of human ovarian cancer cells to antiprogestin-induced cytotoxicity. J Ovarian Res. 2014;7:45.CrossRefPubMedPubMedCentral
3.
Zurück zum Zitat Poornima P, Quency RS, Padma VV. Neferine induces reactive oxygen species mediated intrinsic pathway of apoptosis in hepg2 cells. Food Chem. 2013;136:659–67.CrossRefPubMed Poornima P, Quency RS, Padma VV. Neferine induces reactive oxygen species mediated intrinsic pathway of apoptosis in hepg2 cells. Food Chem. 2013;136:659–67.CrossRefPubMed
4.
Zurück zum Zitat Poornima P, Weng CF, Padma VV. Neferine, an alkaloid from lotus seed embryo, inhibits human lung cancer cell growth by mapk activation and cell cycle arrest. Biofactors. 2014;40:121–31.CrossRefPubMed Poornima P, Weng CF, Padma VV. Neferine, an alkaloid from lotus seed embryo, inhibits human lung cancer cell growth by mapk activation and cell cycle arrest. Biofactors. 2014;40:121–31.CrossRefPubMed
5.
Zurück zum Zitat Zhang X, Liu Z, Xu B, Sun Z, Gong Y, Shao C. Neferine, an alkaloid ingredient in lotus seed embryo, inhibits proliferation of human osteosarcoma cells by promoting p38 mapk-mediated p21 stabilization. Eur J Pharmacol. 2012;677:47–54.CrossRefPubMed Zhang X, Liu Z, Xu B, Sun Z, Gong Y, Shao C. Neferine, an alkaloid ingredient in lotus seed embryo, inhibits proliferation of human osteosarcoma cells by promoting p38 mapk-mediated p21 stabilization. Eur J Pharmacol. 2012;677:47–54.CrossRefPubMed
6.
Zurück zum Zitat Li T, Su L, Zhong N, Hao X, Zhong D, Singhal S, et al. Salinomycin induces cell death with autophagy through activation of endoplasmic reticulum stress in human cancer cells. Autophagy. 2013;9:1057–68.CrossRefPubMedPubMedCentral Li T, Su L, Zhong N, Hao X, Zhong D, Singhal S, et al. Salinomycin induces cell death with autophagy through activation of endoplasmic reticulum stress in human cancer cells. Autophagy. 2013;9:1057–68.CrossRefPubMedPubMedCentral
7.
Zurück zum Zitat Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 2005;5:726–34.CrossRefPubMed Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 2005;5:726–34.CrossRefPubMed
9.
Zurück zum Zitat Moretti L, Yang ES, Kim KW, Lu B. Autophagy signaling in cancer and its potential as novel target to improve anticancer therapy. Drug Resist Updat. 2007;10:135–43.CrossRefPubMed Moretti L, Yang ES, Kim KW, Lu B. Autophagy signaling in cancer and its potential as novel target to improve anticancer therapy. Drug Resist Updat. 2007;10:135–43.CrossRefPubMed
10.
Zurück zum Zitat Eisenberg-Lerner A, Bialik S, Simon HU, Kimchi A. Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ. 2009;16:966–75.CrossRefPubMed Eisenberg-Lerner A, Bialik S, Simon HU, Kimchi A. Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ. 2009;16:966–75.CrossRefPubMed
11.
Zurück zum Zitat Viola G, Bortolozzi R, Hamel E, Moro S, Brun P, Castagliuolo I, et al. Mg-2477, a new tubulin inhibitor, induces autophagy through inhibition of the akt/mtor pathway and delayed apoptosis in a549 cells. Biochem Pharmacol. 2012;83:16–26.CrossRefPubMed Viola G, Bortolozzi R, Hamel E, Moro S, Brun P, Castagliuolo I, et al. Mg-2477, a new tubulin inhibitor, induces autophagy through inhibition of the akt/mtor pathway and delayed apoptosis in a549 cells. Biochem Pharmacol. 2012;83:16–26.CrossRefPubMed
12.
Zurück zum Zitat Shan W, Mercado-Uribe I, Zhang J, Rosen D, Zhang S, Wei J, et al. Mucinous adenocarcinoma developed from human fallopian tube epithelial cells through defined genetic modifications. Cell Cycle. 2012;11:2107–13.CrossRefPubMedPubMedCentral Shan W, Mercado-Uribe I, Zhang J, Rosen D, Zhang S, Wei J, et al. Mucinous adenocarcinoma developed from human fallopian tube epithelial cells through defined genetic modifications. Cell Cycle. 2012;11:2107–13.CrossRefPubMedPubMedCentral
13.
Zurück zum Zitat Zhang X, Wang X, Wu T, Li B, Liu T, Wang R, et al. Isoliensinine induces apoptosis in triple-negative human breast cancer cells through ros generation and p38 mapk/jnk activation. Sci Rep. 2015;5:12579.CrossRefPubMedPubMedCentral Zhang X, Wang X, Wu T, Li B, Liu T, Wang R, et al. Isoliensinine induces apoptosis in triple-negative human breast cancer cells through ros generation and p38 mapk/jnk activation. Sci Rep. 2015;5:12579.CrossRefPubMedPubMedCentral
14.
Zurück zum Zitat Bachar-Wikstrom E, Wikstrom JD, Ariav Y, Tirosh B, Kaiser N, Cerasi E, et al. Stimulation of autophagy improves endoplasmic reticulum stress-induced diabetes. Diabetes. 2013;62:1227–37.CrossRefPubMedPubMedCentral Bachar-Wikstrom E, Wikstrom JD, Ariav Y, Tirosh B, Kaiser N, Cerasi E, et al. Stimulation of autophagy improves endoplasmic reticulum stress-induced diabetes. Diabetes. 2013;62:1227–37.CrossRefPubMedPubMedCentral
15.
Zurück zum Zitat Heras-Sandoval D, Perez-Rojas JM, Hernandez-Damian J, Pedraza-Chaverri J. The role of pi3k/akt/mtor pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell Signal. 2014;26:2694–701.CrossRefPubMed Heras-Sandoval D, Perez-Rojas JM, Hernandez-Damian J, Pedraza-Chaverri J. The role of pi3k/akt/mtor pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell Signal. 2014;26:2694–701.CrossRefPubMed
16.
Zurück zum Zitat Heinonen H, Nieminen A, Saarela M, Kallioniemi A, Klefstrom J, Hautaniemi S, et al. Deciphering downstream gene targets of pi3k/mtor/p70s6k pathway in breast cancer. BMC Genomics. 2008;9:348.CrossRefPubMedPubMedCentral Heinonen H, Nieminen A, Saarela M, Kallioniemi A, Klefstrom J, Hautaniemi S, et al. Deciphering downstream gene targets of pi3k/mtor/p70s6k pathway in breast cancer. BMC Genomics. 2008;9:348.CrossRefPubMedPubMedCentral
17.
19.
Zurück zum Zitat Sahani MH, Itakura E, Mizushima N. Expression of the autophagy substrate sqstm1/p62 is restored during prolonged starvation depending on transcriptional upregulation and autophagy-derived amino acids. Autophagy. 2014;10:431–41.CrossRefPubMedPubMedCentral Sahani MH, Itakura E, Mizushima N. Expression of the autophagy substrate sqstm1/p62 is restored during prolonged starvation depending on transcriptional upregulation and autophagy-derived amino acids. Autophagy. 2014;10:431–41.CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Poornima P, Weng CF, Padma VV. Neferine from nelumbo nucifera induces autophagy through the inhibition of pi3k/akt/mtor pathway and ros hyper generation in a549 cells. Food Chem. 2013;141:3598–605.CrossRefPubMed Poornima P, Weng CF, Padma VV. Neferine from nelumbo nucifera induces autophagy through the inhibition of pi3k/akt/mtor pathway and ros hyper generation in a549 cells. Food Chem. 2013;141:3598–605.CrossRefPubMed
21.
Zurück zum Zitat Wong VK, Wu AG, Wang JR, Liu L, Law BY. Neferine attenuates the protein level and toxicity of mutant huntingtin in pc-12 cells via induction of autophagy. Molecules. 2015;20:3496–514.CrossRefPubMed Wong VK, Wu AG, Wang JR, Liu L, Law BY. Neferine attenuates the protein level and toxicity of mutant huntingtin in pc-12 cells via induction of autophagy. Molecules. 2015;20:3496–514.CrossRefPubMed
22.
Zurück zum Zitat Chen W, Liu L, Luo Y, Odaka Y, Awate S, Zhou H, et al. Cryptotanshinone activates p38/jnk and inhibits erk1/2 leading to caspase-independent cell death in tumor cells. Cancer Prev Res (Phila). 2012;5:778–87.CrossRef Chen W, Liu L, Luo Y, Odaka Y, Awate S, Zhou H, et al. Cryptotanshinone activates p38/jnk and inhibits erk1/2 leading to caspase-independent cell death in tumor cells. Cancer Prev Res (Phila). 2012;5:778–87.CrossRef
23.
Zurück zum Zitat Kang YH, Lee SJ. The role of p38 mapk and jnk in arsenic trioxide-induced mitochondrial cell death in human cervical cancer cells. J Cell Physiol. 2008;217:23–33.CrossRefPubMed Kang YH, Lee SJ. The role of p38 mapk and jnk in arsenic trioxide-induced mitochondrial cell death in human cervical cancer cells. J Cell Physiol. 2008;217:23–33.CrossRefPubMed
24.
Zurück zum Zitat Zikaki K, Aggeli IK, Gaitanaki C, Beis I. Curcumin induces the apoptotic intrinsic pathway via upregulation of reactive oxygen species and jnks in h9c2 cardiac myoblasts. Apoptosis. 2014;19:958–74.CrossRefPubMed Zikaki K, Aggeli IK, Gaitanaki C, Beis I. Curcumin induces the apoptotic intrinsic pathway via upregulation of reactive oxygen species and jnks in h9c2 cardiac myoblasts. Apoptosis. 2014;19:958–74.CrossRefPubMed
25.
Zurück zum Zitat Avisetti DR, Babu KS, Kalivendi SV. Activation of p38/jnk pathway is responsible for embelin induced apoptosis in lung cancer cells: transitional role of reactive oxygen species. PLoS One. 2014;9:e87050.CrossRefPubMedPubMedCentral Avisetti DR, Babu KS, Kalivendi SV. Activation of p38/jnk pathway is responsible for embelin induced apoptosis in lung cancer cells: transitional role of reactive oxygen species. PLoS One. 2014;9:e87050.CrossRefPubMedPubMedCentral
Metadaten
Titel
Neferine induces autophagy of human ovarian cancer cells via p38 MAPK/ JNK activation
verfasst von
Limei Xu
Xiyu Zhang
Yinuo Li
Shuhua Lu
Shan Lu
Jieyin Li
Yuqiong Wang
Xiaoxue Tian
Jian-jun Wei
Changshun Shao
Zhaojian Liu
Publikationsdatum
07.01.2016
Verlag
Springer Netherlands
Erschienen in
Tumor Biology / Ausgabe 7/2016
Print ISSN: 1010-4283
Elektronische ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-4737-8

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