Apicidin inhibits cell growth by downregulating IGF-1R in salivary mucoepidermoid carcinoma cells

Ahn,Mee-Young; Ahn,Ji-Wee; Kim,Hyung-Sik; Lee,Jun; Yoon,Jung-Hoon

doi:10.3892/or.2015.3776

Apicidin inhibits cell growth by downregulating IGF-1R in salivary mucoepidermoid carcinoma cells

Authors:
- Mee-Young Ahn
- Ji-Wee Ahn
- Hyung-Sik Kim
- Jun Lee
- Jung-Hoon Yoon
View Affiliations

Affiliations: Department of Oral and Maxillofacial Pathology, College of Dentistry, Wonkwang Bone Regeneration Research Institute, Daejeon Dental Hospital, Wonkwang University, Daejeon 302-120, Republic of Korea, Division of Toxicology, School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea, Department of Oral and Maxillofacial Surgery, College of Dentistry, Wonkwang Bone Regeneration Research Institute, Daejeon Dental Hospital, Wonkwang University, Daejeon 302-120, Republic of Korea
Published online on: February 2, 2015 https://doi.org/10.3892/or.2015.3776
Pages: 1899-1907

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Inhibition of histone deacetylases (HDACs) has emerged as a new target for cancer therapies. The present study examined the antitumor effect and molecular mechanism of the HDAC inhibitor apicidin in YD-15 human salivary mucoepidermoid carcinoma (MEC) cells. The cells were treated with apicidin and cell death was quantified using an MTT assay. Apoptosis and autophagy were measured using flow cytometry, immunoblot analysis and cell staining. Regulation of the signaling pathways was monitored using immunoblot analysis and co-treatment with specific inhibitors. Insulin-like growth factor 1 receptor (IGF-1R) was knocked down using specific siRNA. Apicidin significantly inhibited the proliferation of MEC cells. Apicidin also induced apoptosis through the inactivation of extracellular signal-regulated kinase (ERK) and AKT/mTOR signaling and activation of c-Jun NH2-terminal kinase (JNK), whereas apicidin promoted autophagy through inactivation of the AKT/mTOR signaling. These effects may be mediated by the inhibition of IGF-1R, an upstream regulator of MAPK and AKT/mTOR pathways. These results suggested that apicidin is an attractive chemotherapeutic agent against salivary MEC and may be a good candidate for targeting IGF-1R for cancer therapies.

View Figures

View References

1	Kim HJ and Bae SC: Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am J Transl Res. 3:166–179. 2011.PubMed/NCBI
2	Grunstein M: Histone acetylation in chromatin structure and transcription. Nature. 389:349–352. 1997. View Article : Google Scholar : PubMed/NCBI
3	Miller CP, Singh MM, Rivera-Del Valle N, Manton CA and Chandra J: Therapeutic strategies to enhance the anti-cancer efficacy of histone deacetylase inhibitors. J Biomed Biotechnol. 2011:5142612011. View Article : Google Scholar
4	Carew JS, Giles FJ and Nawrocki ST: Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett. 269:7–17. 2008. View Article : Google Scholar : PubMed/NCBI
5	Spiegel S, Milstien S and Grant S: Endogenous modulators and pharmacological inhibitors of histone deacetylases in cancer therapy. Oncogene. 31:537–551. 2012.
6	Jung M: Inhibitors of histone deacetylase as new anticancer agents. Curr Med Chem. 8:1505–1511. 2001. View Article : Google Scholar : PubMed/NCBI
7	Darkin-Rattray SJ, Gurnett AM, Myers RW, et al: Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase. Proc Natl Acad Sci USA. 93:13143–13147. 1996. View Article : Google Scholar : PubMed/NCBI
8	Ahn MY, Na YJ, Lee JW, Lee BM and Kim HS: Apicidin induces apoptosis via Cytochrome c-mediated intrinsic pathway in human ovarian cancer cells. Biomol Ther. 17:17–24. 2009. View Article : Google Scholar
9	Im JY, Park H, Kang KW, Choi WS and Kim HS: Modulation of cell cycles and apoptosis by apicidin in estrogen receptor (ER)-positive and-negative human breast cancer cells. Chem Biol Interact. 172:235–244. 2008. View Article : Google Scholar : PubMed/NCBI
10	Ahn MY, Lee J, Na YJ, Choi WS, Lee BM, Kang KW and Kim HS: Mechanism of apicidin-induced cell cycle arrest and apoptosis in Ishikawa human endometrial cancer cells. Chem Biol Interact. 179:169–177. 2009. View Article : Google Scholar
11	Choi KH, Shim JH, Huong LD, Cho NP and Cho SD: Inhibition of myeloid cell leukemia-1 by tolfenamic acid induces apoptosis in mucoepidermoid carcinoma. Oral Dis. 17:469–475. 2011. View Article : Google Scholar : PubMed/NCBI
12	Shen S, Kepp O, Michaud M, et al: Association and dissociation of autophagy, apoptosis and necrosis by systematic chemical study. Oncogene. 30:4544–4556. 2011. View Article : Google Scholar : PubMed/NCBI
13	Portt L, Norman G, Clapp C, Greenwood M and Greenwood MT: Anti-apoptosis and cell survival: a review. Biochim Biophys Acta. 1813:238–259. 2011. View Article : Google Scholar
14	Janku F, McConkey DJ, Hong DS and Kurzrock R: Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol. 8:528–539. 2011. View Article : Google Scholar : PubMed/NCBI
15	Carew JS, Nawrocki ST and Cleveland JL: Modulating autophagy for therapeutic benefit. Autophagy. 3:464–467. 2007. View Article : Google Scholar : PubMed/NCBI
16	Rikiish H: Autophagic and apoptotic effects of HDAC inhibitors on cancer cells. J Biomed Biotechnol. 2011:8302602011.
17	Amaravadi RK and Thompson DB: The roles of therapy-induced autophagy and necrosis in cancer treatment. Clin Cancer Res. 13:7271–7279. 2007. View Article : Google Scholar : PubMed/NCBI
18	Ahn MY, Ahn SG and Yoon JH: Apicidin, a histone deaceylase inhibitor, induces both apoptosis and autophagy in human oral squamous carcinoma cells. Oral Oncol. 47:1032–1038. 2011. View Article : Google Scholar : PubMed/NCBI
19	Lee EJ, Kim J, Lee SA, Kim EJ, Chun YC, Ryu MH and Yook JI: Characterization of newly established oral cancer cell lines derived from six squamous cell carcinoma and two mucoepidermoid carcinoma cells. Exp Mol Med. 37:379–390. 2005. View Article : Google Scholar : PubMed/NCBI
20	Kanematsu S, Uehara N, Miki H, Yoshizawa K, Kawanaka A, Yuri T and Tsubura A: Autophagy inhibition enhances sulforaphane-induced apoptosis in human breast cancer cells. Anticancer Res. 30:3381–3390. 2010.PubMed/NCBI
21	Warnken M, Reitzenstein U, Sommer A, et al: Characterization of proliferative effects of insulin, insulin analogues and insulin-like growth factor-1 (IGF-1) in human lung fibroblasts. Naunyn Schmiedebergs Arch Pharmacol. 382:511–524. 2010. View Article : Google Scholar : PubMed/NCBI
22	Brunet A and Pouyssegur J: Mammalian MAP kinase modules: how to transduce specific signals. Essays Biochem. 32:1–16. 1997.PubMed/NCBI
23	LeRoith D and Roberts CT Jr: The insulin-like growth factor system and cancer. Cancer Lett. 195:127–137. 2003. View Article : Google Scholar : PubMed/NCBI
24	Lalami Y, Vereecken P, Dequanter D, Lothaire P and Awada A: Salivary gland carcinomas, paranasal sinus cancers and melanoma of the head and neck: an update about rare but challenging tumors. Curr Opin Oncol. 18:258–265. 2006. View Article : Google Scholar : PubMed/NCBI
25	McHugh CH, Roberts DB, El-Naggar AK, et al: Prognostic factors in mucoepidermoid carcinoma of the salivary glands. Cancer. 118:3928–3936. 2012. View Article : Google Scholar
26	Kanzawa T, Germano IM, Komata T, Ito H, Kond Y and Kondo S: Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ. 11:448–457. 2004. View Article : Google Scholar : PubMed/NCBI
27	Shao Y, Gao Z, Marks PA and Jiang X: Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci USA. 101:18030–18035. 2004. View Article : Google Scholar : PubMed/NCBI
28	Liu YL, Yang PM, Shun CT, Wu MS, Weng JR and Chem CC: Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma. Autophagy. 6:1057–1065. 2010. View Article : Google Scholar : PubMed/NCBI
29	Amaravadi RK, Yu D, Lum JJ, et al: Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest. 117:326–336. 2007. View Article : Google Scholar : PubMed/NCBI
30	Boya P, Gonzalez-Polo RA, Casares N, et al: Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol. 25:1025–1040. 2005. View Article : Google Scholar : PubMed/NCBI
31	Yan CH, Liang ZQ, Gu ZL, Yang YP, Reid P and Qin ZH: Contributions of autophagic and apoptotic mechanisms to CrTX-induced death of K562 cells. Toxicon. 47:521–530. 2006. View Article : Google Scholar : PubMed/NCBI
32	De Luca A, Maiello MR, D’Alessio A, Pergameno M and Normanno N: The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets. 16:S17–27. 2012. View Article : Google Scholar : PubMed/NCBI
33	Yu C, Friday BB, Lai JP, McCollum A, Atadja P, Roberts LR and Adjei AA: Abrogation of MAPK and Akt signaling by AEE788 synergistically potentiates histone deacetylase inhibitor-induced apoptosis through reactive oxygen species generation. Clin Cancer Res. 13:1140–1148. 2007. View Article : Google Scholar : PubMed/NCBI
34	Sarker D, Reid AH, Yap TA and de Bono JS: Targeting the PI3K/AKT pathway for the treatment of prostate cancer. Clin Cancer Res. 15:4799–4805. 2009. View Article : Google Scholar : PubMed/NCBI
35	Jang ER, Kim YJ, Myung SC, Kim W and Lee CS: Different effect of protein kinase B/Akt and extracellular signal-regulated kinase inhibition on trichostatin A-induced apoptosis in epithelial ovarian carcinoma cell lines. Mol Cell Biochem. 353:1–11. 2011. View Article : Google Scholar : PubMed/NCBI
36	Nishioka C, Ikezoe T, Yang J, Koeffler HP and Yokoyama A: Inhibition of MEK/ERK signaling synergistically potentiates histone deacetylase inhibitor-induced growth arrest, apoptosis and acetylation of histone H3 on p21waf1 promoter in acute myelogenous leukemia cell. Leukemia. 22:1449–1452. 2008. View Article : Google Scholar : PubMed/NCBI
37	Kennedy SG, Wagner AJ, Conzen SD, Jordan J, Bellacosa A, Tsichlis PN and Hay N: The PI 3-kinase/Akt signaling pathway delivers an antiapoptotic signal. Genes Dev. 11:701–713. 1997. View Article : Google Scholar : PubMed/NCBI
38	Widmann C, Gibson S, Jarpe MB and Johnson GL: Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev. 79:143–180. 1999.PubMed/NCBI
39	Takeuchi H, Kanzawa T, Kondo Y and Kondo S: Inhibition of platelet-derived growth factor signaling induces autophagy in malignant glioma cells. Br J Cancer. 90:1069–1075. 2004. View Article : Google Scholar : PubMed/NCBI
40	Mochizuki T, Asai A, Saito N, et al: Akt protein kinase inhibits non-apoptotic programmed cell death induced by ceramide. J Biol Chem. 277:2790–2797. 2002. View Article : Google Scholar
41	Ellington AA, Berhow MA and Singletary KW: Inhibition of Akt signaling and enhanced ERK1/2 activity are involved in induction of macroautophagy by triterpenoid B-group soyasaponins in colon cancer cells. Carcinogenesis. 27:298–306. 2006. View Article : Google Scholar
42	Riedemann J and Macaulay VM: IGF1R signalling and its inhibition. Endocr Relat Cancer. 13:S33–43. 2006. View Article : Google Scholar
43	Obara K, Ide F, Mishima K, Inoue H, Yamada H, Hayashi Y and Saito I: Biological and oncogenic properties of p53-deficient salivary gland epithelial cells with particular emphasis on stromal-epithelial interactions in tumorigenesis. Pathobiology. 73:261–270. 2006. View Article : Google Scholar
44	Mitsiades CS, Mitsiades NS, McMullan CJ, et al: Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA. 101:540–545. 2004. View Article : Google Scholar :
45	Kim SO, Choi BT, Choi IW, et al: Anti-invasive activity of histone deacetylase inhibitors via the induction of Egr-1 and the modulation of tight junction-related proteins in human hepatocarcinoma cells. BMB Rep. 42:655–660. 2009. View Article : Google Scholar : PubMed/NCBI