Honokiol induces apoptosis and suppresses migration and invasion of ovarian carcinoma cells via AMPK/mTOR signaling pathway

Lee,Jin   Sun; Sul,Ji  Young; Park,Jun   Beom; Lee,Myung   Sun; Cha,Eun   Young; Ko,Young   Bok

doi:10.3892/ijmm.2019.4122

Honokiol induces apoptosis and suppresses migration and invasion of ovarian carcinoma cells via AMPK/mTOR signaling pathway

Authors:
- Jin Sun Lee
- Ji Young Sul
- Jun Beom Park
- Myung Sun Lee
- Eun Young Cha
- Young Bok Ko
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Affiliations: Department of Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea, Surgical Oncology Research Laboratory, Chungnam National University Hospital, Daejeon 35015, Republic of Korea, Research Institute for Medicinal Sciences, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
Published online on: March 5, 2019 https://doi.org/10.3892/ijmm.2019.4122
Pages: 1969-1978
Copyright: © Lee et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Honokiol, a natural biphenolic compound, exerts anticancer effects through a variety of mechanisms on multiple types of cancer with relatively low toxicity. Adenosine 5'‑phosphate‑activated protein kinase (AMPK), an essential regulator of cellular homeostasis, may control cancer progression. The present study aimed to investigate whether the anticancer activities of honokiol in ovarian cancer cells were mediated through the activation of AMPK. Honokiol decreased cell viability of 2 ovarian cancer cell lines, with an half‑maximal inhibitory concentration value of 48.71±11.31 µM for SKOV3 cells and 46.42±5.37 µM for Caov‑3 cells. Honokiol induced apoptosis via activation of caspase‑3, caspase‑7 and caspase‑9, and cleavage of poly‑(adenosine 5'‑diphosphate‑ribose) polymerase. Apoptosis induced by honokiol was weakened by compound C, an AMPK inhibitor, suggesting that honokiol‑induced apoptosis was dependent on the AMPK/mechanistic target of rapamycin signaling pathway. Additionally, honokiol inhibited the migration and invasion of ovarian cancer cells. The combined treatment of honokiol with compound C reversed the activities of honokiol in wound healing and Matrigel invasion assays. These results indicated that honokiol may have therapeutic potential in ovarian cancer by targeting AMPK activation.

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1	Hoskins WJ, McGuire WP, Brady MF, Homesley HD, Creasman WT, Berman M, Ball H and Berek JS: The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol. 170:974–979. 1994. View Article : Google Scholar : PubMed/NCBI
2	Liu Y, Chen L, He X, Fan L, Yang G, Chen X, Lin X, DU L, Li Z, Ye H, et al: Enhancement of therapeutic effectiveness by combining liposomal honokiol with cisplatin in ovarian carcinoma. Int J Gynecol Cancer. 18:652–659. 2008. View Article : Google Scholar
3	Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, Mannel RS, DeGeest K, Hartenbach EM and Baergen R; Gynecologic Oncology Group: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A gynecologic oncology group study. J Clin Oncol. 21:3194–3200. 2003. View Article : Google Scholar : PubMed/NCBI
4	Hardie DG: Sensing of energy and nutrients by AMP-activated protein kinase. Am J Clin Nutr. 93:891S–896S. 2011. View Article : Google Scholar : PubMed/NCBI
5	Wright JL and Stanford JL: Metformin use and prostate cancer in caucasian men: Results from a population-based case-control study. Cancer Causes Control. 20:1617–1622. 2009. View Article : Google Scholar : PubMed/NCBI
6	Henderson D, Frieson D, Zuber J and Solomon SS: Metformin has positive therapeutic effects in colon cancer and lung cancer. Am J Med Sci. 354:246–251. 2017. View Article : Google Scholar : PubMed/NCBI
7	Bodmer M, Meier C, Krähenbühl S, Jick SS and Meier CR: Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care. 33:1304–1308. 2010. View Article : Google Scholar : PubMed/NCBI
8	Li D, Yeung SC, Hassan MM, Konopleva M and Abbruzzese JL: Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology. 137:482–488. 2009. View Article : Google Scholar : PubMed/NCBI
9	Dowling RJ, Zakikhani M, Fantus IG, Pollak M and Sonenberg N: Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res. 67:10804–10812. 2007. View Article : Google Scholar : PubMed/NCBI
10	Wang LW, Li ZS, Zou DW, Jin ZD, Gao J and Xu GM: Metformin induces apoptosis of pancreatic cancer cells. World J Gastroenterol. 14:7192–7198. 2008. View Article : Google Scholar : PubMed/NCBI
11	He XX, Tu SM, Lee MH and Yeung SC: Thiazolidinediones and metformin associated with improved survival of diabetic prostate cancer patients. Ann Oncol. 22:2640–2645. 2011. View Article : Google Scholar : PubMed/NCBI
12	Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, Hsu L, Hung MC, Hortobagyi GN and Gonzalez-Angulo AM: Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 27:3297–3302. 2009. View Article : Google Scholar : PubMed/NCBI
13	Kirpichnikov D, McFarlane SI and Sowers JR: Metformin: An update. Ann Intern Med. 137:25–33. 2002. View Article : Google Scholar : PubMed/NCBI
14	Zong H, Yin B, Zhou H, Cai D, Ma B and Xiang Y: Inhibition of mTOR pathway attenuates migration and invasion of gallbladder cancer via EMT inhibition. Mol Biol Rep. 41:4507–4512. 2014. View Article : Google Scholar : PubMed/NCBI
15	Inoki K, Kim J and Guan KL: AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharmacol Toxicol. 52:381–400. 2012. View Article : Google Scholar
16	Chapuis N, Tamburini J, Green AS, Willems L, Bardet V, Park S, Lacombe C, Mayeux P and Bouscary D: Perspectives on inhibiting mTOR as a future treatment strategy for hematological malignancies. Leukemia. 24:1686–1699. 2010. View Article : Google Scholar : PubMed/NCBI
17	Liu J, Wang S, Zhang Y, Fan HT and Lin HS: Traditional chinese medicine and cancer: History, present situation, and development. Thorac Cancer. 6:561–569. 2015. View Article : Google Scholar : PubMed/NCBI
18	Seo MS, Hong SW, Yeon SH, Kim YM, Um KA, Kim JH, Kim HJ, Chang KC and Park SW: Magnolia officinalis attenuates free fatty acid-induced lipogenesis via AMPK phosphorylation in hepatocytes. J Ethnopharmacol. 157:140–148. 2014. View Article : Google Scholar : PubMed/NCBI
19	Liu Z, Zhang X, Cui W, Zhang X, Li N, Chen J, Wong AW and Roberts A: Evaluation of short-term and subchronic toxicity of magnolia bark extract in rats. Regul Toxicol Pharmacol. 49:160–171. 2007. View Article : Google Scholar : PubMed/NCBI
20	Sarrica A, Kirika N, Romeo M, Salmona M and Diomede L: Safety and toxicology of magnolol and honokiol. Planta Med. 84:1151–1164. 2018. View Article : Google Scholar : PubMed/NCBI
21	Fried LE and Arbiser JL: Honokiol, a multifunctional antiangiogenic and antitumor agent. Antioxid Redox Signal. 11:1139–1148. 2009. View Article : Google Scholar : PubMed/NCBI
22	Steinmann P, Walters DK, Arlt MJ, Banke IJ, Ziegler U, Langsam B, Arbiser J, Muff R, Born W and Fuchs B: Antimetastatic activity of honokiol in osteosarcoma. Cancer. 118:2117–2127. 2012. View Article : Google Scholar
23	Park EJ, Min HY, Chung HJ, Hong JY, Kang YJ, Hung TM, Youn UJ, Kim YS, Bae K, Kang SS and Lee SK: Down-regulation of c-Src/EGFR-mediated signaling activation is involved in the honokiol-induced cell cycle arrest and apoptosis in MDA-MB-231 human breast cancer cells. Cancer Lett. 277:133–140. 2009. View Article : Google Scholar : PubMed/NCBI
24	Ishikawa C, Arbiser JL and Mori N: Honokiol induces cell cycle arrest and apoptosis via inhibition of survival signals in adult T-cell leukemia. Biochim Biophys Acta. 1820:879–887. 2012. View Article : Google Scholar : PubMed/NCBI
25	Yeh PS, Wang W, Chang YA, Lin CJ, Wang JJ and Chen RM: Honokiol induces autophagy of neuroblastoma cells through activating the PI3K/Akt/mTOR and endoplasmic reticular stress/ERK1/2 signaling pathways and suppressing cell migration. Cancer Lett. 370:66–77. 2016. View Article : Google Scholar
26	Dai X, Li RZ, Jiang ZB, Wei CL, Luo LX, Yao XJ, Li GP and Leung EL: Honokiol inhibits proliferation, invasion and induces apoptosis through targeting lyn kinase in human lung adenocarcinoma cells. Front Pharmacol. 9:5582018. View Article : Google Scholar : PubMed/NCBI
27	Shen L, Zhang F, Huang R, Yan J and Shen B: Honokiol inhibits bladder cancer cell invasion through repressing SRC-3 expression and epithelial-mesenchymal transition. Oncol Lett. 14:4294–4300. 2017. View Article : Google Scholar : PubMed/NCBI
28	Nagalingam A, Arbiser JL, Bonner MY, Saxena NK and Sharma D: Honokiol activates AMP-activated protein kinase in breast cancer cells via an LKB1-dependent pathway and inhibits breast carcinogenesis. Breast Cancer Res. 14:R352012. View Article : Google Scholar : PubMed/NCBI
29	Singh T and Katiyar SK: Honokiol, a phytochemical from magnolia spp., inhibits breast cancer cell migration by targeting nitric oxide and cyclooxygenase-2. Int J Oncol. 38:769–776. 2011.PubMed/NCBI
30	Kumar A, Kumar Singh U and Chaudhary A: Honokiol analogs: A novel class of anticancer agents targeting cell signaling pathways and other bioactivities. Future Med Chem. 5:809–829. 2013. View Article : Google Scholar : PubMed/NCBI
31	Luo LX, Li Y, Liu ZQ, Fan XX, Duan FG, Li RZ, Yao XJ, Leung EL and Liu L: Honokiol induces apoptosis, G1 arrest, and autophagy in KRAS mutant lung cancer cells. Front Pharmacol. 8:1992017. View Article : Google Scholar : PubMed/NCBI
32	Shigemura K, Arbiser JL, Sun SY, Zayzafoon M, Johnstone PA, Fujisawa M, Gotoh A, Weksler B, Zhau HE and Chung LW: Honokiol, a natural plant product, inhibits the bone metastatic growth of human prostate cancer cells. Cancer. 109:1279–1289. 2007. View Article : Google Scholar : PubMed/NCBI
33	Liu H, Zang C, Emde A, Planas-Silva MD, Rosche M, Kühnl A, Schulz CO, Elstner E, Possinger K and Eucker J: Anti-tumor effect of honokiol alone and in combination with other anticancer agents in breast cancer. Eur J Pharmacol. 591:43–51. 2008. View Article : Google Scholar : PubMed/NCBI
34	Cheng N, Xia T, Han Y, He QJ, Zhao R and Ma JR: Synergistic antitumor effects of liposomal honokiol combined with cisplatin in colon cancer models. Oncol Lett. 2:957–962. 2011.
35	Li Z, Liu Y, Zhao X, Pan X, Yin R, Huang C, Chen L and Wei Y: Honokiol, a natural therapeutic candidate, induces apoptosis and inhibits angiogenesis of ovarian tumor cells. Eur J Obstet Gynecol Reprod Biol. 140:95–102. 2008. View Article : Google Scholar : PubMed/NCBI
36	Kwan HT, Chan DW, Cai PC, Mak CS, Yung MM, Leung TH, Wong OG, Cheung AN and Ngan HY: AMPK activators suppress cervical cancer cell growth through inhibition of DVL3 mediated Wnt/β-catenin signaling activity. PLoS One. 8:e535972013. View Article : Google Scholar
37	Gurumurthy S, Hezel AF, Sahin E, Berger JH, Bosenberg MW and Bardeesy N: LKB1 deficiency sensitizes mice to carcinogen-induced tumorigenesis. Cancer Res. 68:55–63. 2008. View Article : Google Scholar : PubMed/NCBI
38	Chen Y, Liu Y, Zhou Y and You H: Molecular mechanism of LKB1 in the invasion and metastasis of colorectal cancer. Oncol Rep. 41:1035–1044. 2019.
39	Vazquez-Martin A, Oliveras-Ferraros C, Lopez-Bonet E and Menendez JA: AMPK: Evidence for an energy-sensing cytokinetic tumor suppressor. Cell Cycle. 8:3679–3683. 2009. View Article : Google Scholar : PubMed/NCBI
40	Hardie DG: The AMP-activated protein kinase pathway-new players upstream and downstream. J Cell Sci. 117:5479–5487. 2004. View Article : Google Scholar : PubMed/NCBI
41	Duan P, Hu C, Quan C, Yu T, Huang W, Chen W, Tang S, Shi Y, Martin FL and Yang K: 4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in sertoli cells. Toxicol Lett. 267:21–31. 2017. View Article : Google Scholar : PubMed/NCBI
42	Zakikhani M, Dowling R, Fantus IG, Sonenberg N and Pollak M: Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 66:10269–10273. 2006. View Article : Google Scholar : PubMed/NCBI
43	Al-Moujahed A, Nicolaou F, Brodowska K, Papakostas TD, Marmalidou A, Ksander BR, Miller JW, Gragoudas E and Vavvas DG: Uveal melanoma cell growth is inhibited by aminoimidazole carboxamide ribonucleotide (AICAR) partially through activation of AMP-dependent kinase. Invest Ophthalmol Vis Sci. 55:4175–4185. 2014. View Article : Google Scholar : PubMed/NCBI
44	Yung MM, Chan DW, Liu VW, Yao KM and Ngan HY: Activation of AMPK inhibits cervical cancer cell growth through AKT/FOXO3a/FOXM1 signaling cascade. BMC Cancer. 13:3272013. View Article : Google Scholar : PubMed/NCBI
45	Whang YM, Kim MJ, Cho MJ, Yoon H, Choi YW, Kim TH and Chang IH: Rapamycin enhances growth inhibition on urothelial carcinoma cells through LKB1 deficiency-mediated mitochondrial dysregulation. J Cell Physiol. 1–14. 2018.
46	Zhang JW, Zhao F and Sun Q: Metformin synergizes with rapamycin to inhibit the growth of pancreatic cancer in vitro and in vivo. Oncol Lett. 15:1811–1816. 2018.PubMed/NCBI
47	Mukhopadhyay S, Chatterjee A, Kogan D, Patel D and Foster DA: 5-Aminoimidazole-4-carboxamide-1-β-4-ribofura noside (AICAR) enhances the efficacy of rapamycin in human cancer cells. Cell Cycle. 14:3331–3339. 2015. View Article : Google Scholar
48	Arora S, Singh S, Piazza GA, Contreras CM, Panyam J and Singh AP: Honokiol: A novel natural agent for cancer prevention and therapy. Curr Mol Med. 12:1244–1252. 2012. View Article : Google Scholar : PubMed/NCBI
49	Kaushik G, Kwatra D, Subramaniam D, Jensen RA, Anant S and Mammen JM: Honokiol affects melanoma cell growth by targeting the AMP-activated protein kinase signaling pathway. Am J Surg. 208:995–1002. 2014. View Article : Google Scholar : PubMed/NCBI
50	Queiroz EA, Puukila S, Eichler R, Sampaio SC, Forsyth HL, Lees SJ, Barbosa AM, Dekker RF, Fortes ZB and Khaper N: Metformin induces apoptosis and cell cycle arrest mediated by oxidative stress, AMPK and FOXO3a in MCF-7 breast cancer cells. PLoS One. 9. pp. e982072014, View Article : Google Scholar
51	Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, Viollet B and Thompson CB: Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 67:6745–6752. 2007. View Article : Google Scholar : PubMed/NCBI
52	Shin JA, Kwon KH and Cho SD: AMPK-activated protein kinase activation by Impatiens balsamina L. is related to apoptosis in HSC-2 human oral cancer cells. Pharmacogn Mag. 11:136–142. 2015. View Article : Google Scholar : PubMed/NCBI
53	Ferla R, Haspinger E and Surmacz E: Metformin inhibits leptin-induced growth and migration of glioblastoma cells. Oncol Lett. 4:1077–1081. 2012. View Article : Google Scholar : PubMed/NCBI
54	Cheng S, Castillo V, Eliaz I and Sliva D: Honokiol suppresses metastasis of renal cell carcinoma by targeting KISS1/KISS1R signaling. Int J Oncol. 46:2293–2298. 2015. View Article : Google Scholar : PubMed/NCBI