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Archives of Gynecology and Obstetrics

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04.07.2018 | Gynecologic Oncology

Orlistat induces apoptosis and protective autophagy in ovarian cancer cells: involvement of Akt-mTOR-mediated signaling pathway

verfasst von: Hongling Peng, Qiao Wang, Xiaorong Qi, Xi Wang, Xia Zhao

Erschienen in: Archives of Gynecology and Obstetrics | Ausgabe 3/2018

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Abstract

Introduction

Orlistat possesses anti-tumor capacity by inducing apoptosis in ovarian cancer cells. However, the mechanism is not clearly understood. Emerging evidence indicates the overlaps between autophagy and apoptosis. In this study, we have investigated the role of autophagy in orlistat-induced apoptosis in ovarian cancer (OC) cells.

Methods

The effect of orlistat on apoptosis was evaluated in SKOV3 and A2780 cell lines by MTT and TUNEL assay. The formations of autophagosomes were observed by acridine orange and GFP-LC3 fluorescence. In addition, conversions of LC3-I to LC3-II were analyzed by western blot, as well as other autophagy-related proteins. 3-Methyladenine (3-MA) was used as an autophagy inhibitor in combined treatment with orlistat. Western blot was further conducted to investigate the molecular mechanisms of orlistat-affected apoptosis and autophagy on protein level.

Results

The proliferation activities of OC cells were inhibited by orlistat in a dose-dependent manner. The expressions of cleaved-caspase 3 and 9 in orlistat-treated cells were increasing, which suggested that orlistat-induced apoptosis was caspase-dependent. At the same time, the average number of GFP-LC3 dots per cell was increased after 48 h of orlistat treatment. The expression levels of LC3-II were significantly up-regulated, as well as other autophagy-related proteins such as Vsp34, Atg7 and UVRAG. These results suggested orlistat-induced autophagy flux, which was further found involved in inhibiting the Akt/mTOR/p70S6K signaling pathway. However, combined treatment of orlistat and 3-MA significantly suppressed the cell viability, which indicated a pro-survival role of autophagy in OC cells.

Conclusion

We suggested that orlistat had anti-cancer effect in OC cells. In addition, autophagy played a pro-survival role, suppressing which the orlistat-induced anti-cancer effect would be more significant.

White KL, Schildkraut JM, Palmieri RT et al (2012) Ovarian cancer risk associated with inherited inflammation-related variants. Cancer Res 72(5):1064–1069CrossRefPubMedPubMedCentral

Maier T, Leibundgut M, Boehringer D et al (2010) Structure and function of eukaryotic fatty acid synthases. Q Rev Biophys 43:373–422CrossRefPubMed

Gelebart P, Zak Z, Anand M et al (2012) Blockade of fatty acid synthase triggers significant apoptosis in mantle cell lymphoma. PLoS One 7(4):e33738. https://doi.org/10.1371/journal.pone.0033738 CrossRefPubMedPubMedCentral

Puig T, Aguilar H, Cufi S et al (2011) A novel inhibitor of fatty acid synthase shows activity against HER2+ breast cancer xenografts and is active in anti-HER2 drug-resistant cell lines. Breast Cancer Res 13(6):R131. https://doi.org/10.1186/bcr3077 CrossRefPubMedPubMedCentral

Zaytseva YY, Rychahou PG, Gulhati P et al (2012) Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer. Cancer Res 72(6):1504–1517. https://doi.org/10.1158/0008-5472.can-11-4057 CrossRefPubMedPubMedCentral

Di Vizio D, Sotgia F, Williams TM et al (2007) Caveolin-1 is required for the upregulation of fatty acid synthase (FASN), a tumor promoter, during prostate cancer progression. Cancer Biol Ther 6:1263–1268CrossRefPubMed

Gansler TS, Hardman W 3rd, Hunt DA, Schaffel S, Hennigar RA (1997) Increased expression of fatty acid synthase (OA-519) in ovarian neoplasms predicts shorter survival. Hum Pathol 28:686–692CrossRefPubMed

Huang HQ, Tang J, Zhou ST et al (2012) Orlistat, a novel potent antitumor agent for ovarian cancer: proteomic analysis of ovarian cancer cells treated with Orlistat. Int J Oncol 41(2):523–532. https://doi.org/10.3892/ijo.2012.1465 CrossRefPubMed

Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205–219CrossRefPubMed

10.

Bossy-Wetzel E, Newmeyer DD, Green DR (1998) Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J 17(1):37–49. https://doi.org/10.1093/emboj/17.1.37 CrossRefPubMedPubMedCentral

11.

Porter AG, Janicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6:99–104CrossRefPubMed

12.

Li P, Nijhawan D, Budihardjo I et al (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91(4):479–489CrossRefPubMed

13.

Pattingre S, Tassa A, Qu X et al (2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122(6):927–939. https://doi.org/10.1016/j.cell.2005.07.002 CrossRefPubMed

14.

Mujumdar N, Saluja AK (2010) Autophagy in pancreatic cancer: an emerging mechanism of cell death. Autophagy 6:997–998CrossRefPubMedPubMedCentral

15.

Yu L, Alva A, Su H et al (2004) Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304(5676):1500–1502. https://doi.org/10.1126/science.1096645 CrossRefPubMed

16.

Zeng X, Kinsella TJ (2008) Mammalian target of rapamycin and S6 kinase 1 positively regulate 6-thioguanine-induced autophagy. Cancer Res 68(7):2384–2390. https://doi.org/10.1158/0008-5472.can-07-6163 CrossRefPubMed

17.

Paglin S, Hollister T, Delohery T et al (2001) A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res 61:439–444PubMed

18.

Rosenfeldt MT, Ryan KM (2011) The multiple roles of autophagy in cancer. Carcinogenesis 32:955–963CrossRefPubMedPubMedCentral

19.

Jaber N, Dou Z, Chen JS et al (2012) Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function. Proc Natl Acad Sci USA 109(6):2003–2008. https://doi.org/10.1073/pnas.1112848109 CrossRefPubMed

20.

Zhao Z, Ni D, Ghozalli I, Pirooz SD et al (2012) UVRAG: at the crossroad of autophagy and genomic stability. Autophagy 8:1392–1393CrossRefPubMedPubMedCentral

21.

Codogno P, Meijer AJ (2005) Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ 12(Suppl 2):1509–1518. https://doi.org/10.1038/sj.cdd.4401751 CrossRefPubMed

22.

Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70CrossRefPubMed

23.

Schuhr CA, Eisenreich W, Goese M et al (2002) Biosynthetic precursors of the lipase inhibitor lipstatin. J Org Chem 67:2257–2262CrossRefPubMed

24.

Chuang HY, Chang YF, Hwang JJ (2011) Antitumor effect of orlistat, a fatty acid synthase inhibitor, is via activation of caspase-3 on human colorectal carcinoma-bearing animal. Biomed Pharmacother 65(4):286–292. https://doi.org/10.1016/j.biopha.2011.02.016 CrossRefPubMed

25.

Fujiwara J, Sowa Y, Horinaka M et al (2011) The anti-obesity drug orlistat promotes sensitivity to TRAIL by two different pathways in hormone-refractory prostate cancer cells. Int J Oncol 40(5):1483–1491. https://doi.org/10.3892/ijo.2012.1353 CrossRef

26.

Seguin F, Carvalho MA, Bastos DC et al (2012) The fatty acid synthase inhibitor orlistat reduces experimental metastases and angiogenesis in B16-F10 melanomas. Br J Cancer. https://doi.org/10.1038/bjc.2012.355 PubMedPubMedCentralCrossRef

27.

Mizushima N, Levine B, Cuervo AM et al (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075CrossRefPubMedPubMedCentral

28.

Hoyer-Hansen M, Jaattela M (2008) Autophagy: an emerging target for cancer therapy. Autophagy 4(5):574–580CrossRefPubMed

29.

Kondo Y, Kanzawa T, Sawaya R et al (2005) The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 5(9):726–734. https://doi.org/10.1038/nrc1692 CrossRefPubMed

30.

Kanzawa T, Kondo Y, Ito H, Kondo S et al (2003) Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. Cancer Res 63(9):2103–2108PubMed

31.

Chen YJ, Huang WP, Yang YC et al (2009) Platonin induces autophagy-associated cell death in human leukemia cells. Autophagy 5(2):173–183CrossRefPubMed

32.

Thorburn A (2008) Apoptosis and autophagy: regulatory connections between two supposedly different processes. Apoptosis 13(1):1–9. https://doi.org/10.1007/s10495-007-0154-9 CrossRefPubMedPubMedCentral

Titel: Orlistat induces apoptosis and protective autophagy in ovarian cancer cells: involvement of Akt-mTOR-mediated signaling pathway
verfasst von: Hongling Peng
Qiao Wang
Xiaorong Qi
Xi Wang
Xia Zhao
Publikationsdatum: 04.07.2018
Verlag: Springer Berlin Heidelberg
Erschienen in: Archives of Gynecology and Obstetrics / Ausgabe 3/2018
Print ISSN: 0932-0067
Elektronische ISSN: 1432-0711
DOI: https://doi.org/10.1007/s00404-018-4841-2

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Orlistat induces apoptosis and protective autophagy in ovarian cancer cells: involvement of Akt-mTOR-mediated signaling pathway

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Introduction

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Introduction

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