Suppression of cyclooxygenase 2 increases chemosensitivity to sesamin through the Akt‑PI3K signaling pathway in lung cancer cells

Fang,Qing; Zhu,Yuyin; Wang,Qilai; Song,Meijun; Gao,Guosheng; Zhou,Zhiming

doi:10.3892/ijmm.2018.3939

Suppression of cyclooxygenase 2 increases chemosensitivity to sesamin through the Akt‑PI3K signaling pathway in lung cancer cells

Authors:
- Qing Fang
- Yuyin Zhu
- Qilai Wang
- Meijun Song
- Guosheng Gao
- Zhiming Zhou
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Affiliations: Department of Pulmonary Medicine, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315000, P.R. China, Department of Emergency Medicine, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315000, P.R. China, Department of Laboratory, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315000, P.R. China
Published online on: October 18, 2018 https://doi.org/10.3892/ijmm.2018.3939
Pages: 507-516

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Abstract

Safe, affordable and efficacious agents are urgently required for cancer prevention. Sesamin, a lipid‑soluble lignan from sesame (Sesamum indicum) displays anticancer activities through an unknown mechanism. In the present study, the anticancer activity of sesamin via cyclooxygenase 2 (COX2) was investigated in lung cancer. Quantitative polymerase chain reaction was performed to determine the mRNA expression levels of COX2 in cells, while western blot analysis was used to determine its protein expression levels. Cell proliferation was evaluated by Cell Counting Kit‑8 assay, while apoptosis and cell cycle analyses were conducted by flow cytometry. The results indicated that COX2 expression was upregulated in lung cancer cell lines compared with human normal lung epithelial cell line BEAS‑2B and sesamin was demonstrated to decrease the levels of COX2, inhibit the proliferation of lung cancer cells and promote their apoptosis in a concentration‑dependent manner. Furthermore, decreased COX2 expression potentiated sesamin‑induced apoptosis and G1‑phase arrest, which was correlated with the suppression of gene products associated with cell apoptosis (Bcl‑2 and Bax) and the cell cycle (cyclin E1). In addition, cotreatment with the COX2 inhibitor CAY10404 and sesamin downregulated the expression of downstream molecules of COX2 [including interleukin (IL)1β, IL6 and tumor necrosis factor α] compared with CAY10404 or sesamin alone. Furthermore, cotreatment with sesamin and CAY10404 markedly reduced the levels of phosphorylated protein kinase B (pAkt) and phosoinositide 3 kinase (PI3K) in three lung cancer cell lines. PI3K expression was observed to be under the control of COX2, possibly forming a negative feedback loop. In addition, PI3K depletion induced apoptosis and G1‑phase arrest in A549 cells. These results suggested that sesamin blocked the pAkt‑PI3K signaling pathway by downregulating the expression of COX2, therefore resulting in cell cycle arrest and increased apoptosis in vitro. In conclusion, inhibition of COX2 increased the sensitivity of lung cancer cells to sesamin by modulating pAkt‑PI3K signaling. These results may aid the development of more selective agents to overcome cancer.

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1	Salskov A, Hawes SE, Stern JE, Feng Q, Jordan CD, Wiens L, Rasey J, Lu H, Kiviat NB and Vesselle H: Hypermethylation of CCND2 may reflect a smoking-induced precancerous change in the lung. J Oncol. 2011:9501402011. View Article : Google Scholar : PubMed/NCBI
2	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
3	Bao M, Song Y, Xia J, Li P, Liu Q and Wan Z: miR-1269 promotes cell survival and proliferation by targeting tp53 and caspase-9 in lung cancer. Onco Targets Ther. 11:1721–1732. 2018. View Article : Google Scholar : PubMed/NCBI
4	Zheng L, Zhou H, Guo L, Xu X, Zhang S, Xu W and Mao W: Inhibition of NIPBL enhances the chemosensitivity of non-small-cell lung cancer cells via the DNA damage response and autophagy pathway. Onco Targets Ther. 11:1941–1948. 2018. View Article : Google Scholar : PubMed/NCBI
5	Thuy TD, Phan NN, Wang CY, Yu HG, Wang SY, Huang PL, Do YY and Lin YC: Novel therapeutic effects of sesamin on diabetes-induced cardiac dysfunction. Mol Med Rep. 15:2949–2956. 2017. View Article : Google Scholar : PubMed/NCBI
6	Fan D, Yang Z, Yuan Y, Wu QQ, Xu M, Jin YG and Tang QZ: Sesamin prevents apoptosis and inflammation after experimental myocardial infarction by JNK and NF-κB pathways. Food Funct. 8:2875–2885. 2017. View Article : Google Scholar : PubMed/NCBI
7	Qiang L, Yuan J, Shouyin J, Yulin L, Libing J and Jian-An W: Sesamin attenuates lipopolysaccharide-induced acute lung injury by inhibition of TLR4 signaling pathways. Inflammation. 39:467–472. 2016. View Article : Google Scholar
8	Xu P, Cai F, Liu X and Guo L: Sesamin inhibits lipopolysaccha-ride-induced proliferation and invasion through the p38-MAPK and NF-kappaB signaling pathways in prostate cancer cells. Oncol Rep. 33:3117–3123. 2015. View Article : Google Scholar : PubMed/NCBI
9	Kuang W, Deng Q, Deng C, Li W, Shu S and Zhou M: Hepatocyte growth factor induces breast cancer cell invasion via the PI3K/Akt and p38 MAPK signaling pathways to up-regulate the expression of COX2. Am J Transl Res. 9:3816–3826. 2017.PubMed/NCBI
10	Chun KS and Surh YJ: Signal transduction pathways regulating cyclooxygenase-2 expression: Potential molecular targets for chemoprevention. Biochem Pharmacol. 68:1089–1100. 2004. View Article : Google Scholar : PubMed/NCBI
11	Spano JP, Chouahnia K and Morere JF: Cyclooxygenase 2 inhibitors and lung carcinoma. Bull Cancer. 91(S109-S112)2004.In French.
12	Yang CL, Zheng XL, Ye K, Ge H, Sun YN, Lu YF and Fan QX: MicroRNA-183 acts as a tumor suppressor in human non-small cell lung cancer by down-regulating MTA1. Cell Physiol Biochem. 46:93–106. 2018. View Article : Google Scholar : PubMed/NCBI
13	Yin H, Ma J, Chen L, Piao S, Zhang Y, Zhang S, Ma H, Li Y, Qu Y, Wang X and Xu Q: MiR-99a enhances the radiation sensitivity of non-small cell lung cancer by targeting mTOR. Cell Physiol Biochem. 46:471–481. 2018. View Article : Google Scholar : PubMed/NCBI
14	Jiang SX, Qi B, Yao WJ, Gu CW, Wei XF, Zhao Y, Liu YZ and Zhao BS: Berberine displays antitumor activity in esophageal cancer cells in vitro. World J Gastroenterol. 23:2511–2518. 2017. View Article : Google Scholar : PubMed/NCBI
15	Xiao H, Liu Y, Liang P, Wang B, Tan H, Zhang Y, Gao X and Gao J: TP53TG1 enhances cisplatin sensitivity of non-small cell lung cancer cells through regulating miR-18a/PTEN axis. Cell Biosci. 8:232018. View Article : Google Scholar : PubMed/NCBI
16	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T) method. Methods. 25:402–408. 2001. View Article : Google Scholar
17	Zhuang H, Meng X, Li Y, Wang X, Huang S, Liu K, Hehir M, Fang R, Jiang L, Zhou JX, et al: Cyclic AMP responsive element-binding protein promotes renal cell carcinoma proliferation probably via the expression of spindle and kinetochore-associated protein 2. Oncotarget. 7:16325–16337. 2016. View Article : Google Scholar : PubMed/NCBI
18	Yoon KY, Kim KJ, Youn HS, Oh SR and Lee BY: Brazilin suppresses inflammation via the down-regulation of IRAK4 in LPS-stimulated Raw264.7 Macrophage. J Food Nutri Res. 3:575–580. 2015. View Article : Google Scholar
19	Alam SK, Astone M, Liu P, Hall SR, Coyle AM, Dankert EN, Hoffman DK, Zhang W, Kuang R, Roden AC, et al: DARPP-32 and t-DARPP promote non-small cell lung cancer growth through regulation of IKKα-dependent cell migration. Commun Biol. 1:432018. View Article : Google Scholar
20	Kong X, Ma MZ, Zhang Y, Weng MZ, Gong W, Guo LQ, Zhang JX, Wang GD, Su Q, Quan ZW and Yang JR: Differentiation therapy: Sesamin as an effective agent in targeting cancer stem-like side population cells of human gallbladder carcinoma. BMC Complement Altern Med. 14:2542014. View Article : Google Scholar : PubMed/NCBI
21	Akl MR, Ayoub NM and Sylvester PW: Mechanisms mediating the synergistic anticancer effects of combined γ-tocotrienol and sesamin treatment. Planta Med. 78:1731–1739. 2012. View Article : Google Scholar : PubMed/NCBI
22	Deng P, Wang C, Chen L, Wang C, Du Y, Yan X, Chen M, Yang G and He G: Sesamin induces cell cycle arrest and apoptosis through the inhibition of signal transducer and activator of transcription 3 signalling in human hepatocellular carcinoma cell line HepG2. Biol Pharm Bull. 36:1540–1548. 2013. View Article : Google Scholar : PubMed/NCBI
23	Harikumar KB, Sung B, Tharakan ST, Pandey MK, Joy B, Guha S, Krishnan S and Aggarwal BB: Sesamin manifests chemopreventive effects through the suppression of NF-kappa B-regulated cell survival, proliferation, invasion, and angiogenic gene products. Mol Cancer Res. 8:751–761. 2010. View Article : Google Scholar : PubMed/NCBI
24	Dhakal HP, Naume B, Synnestvedt M, Borgen E, Kaaresen R, Schlichting E, Wiedswang G, Bassarova A, Holm R, Giercksky KE and Nesland JM: Expression of cyclooxygenase-2 in invasive breast carcinomas and its prognostic impact. Histol Histopathol. 27:1315–1325. 2012.PubMed/NCBI
25	Karavitis J, Hix LM, Shi YH, Schultz RF, Khazaie K and Zhang M: Regulation of COX2 expression in mouse mammary tumor cells controls bone metastasis and PGE2-induction of regulatory T cell migration. PLoS One. 7:e463422012. View Article : Google Scholar : PubMed/NCBI
26	Shimizu S, Fujii G, Takahashi M, Nakanishi R, Komiya M, Shimura M, Noma N, Onuma W, Terasaki M, Yano T and Mutoh M: Sesamol suppresses cyclooxygenase-2 transcriptional activity in colon cancer cells and modifies intestinal polyp development in Apc (Min/+) mice. J Clin Biochem Nutr. 54:95–101. 2014. View Article : Google Scholar : PubMed/NCBI
27	Wang R, Wang X, Lin F, Gao P, Dong K and Zhang HZ: shRNA-targeted cyclooxygenase (COX)-2 inhibits proliferation, reduces invasion and enhances chemosensitivity in laryngeal carcinoma cells. Mol Cell Biochem. 317:179–188. 2008. View Article : Google Scholar : PubMed/NCBI
28	Li B, Li X, Xiong H, Zhou P, Ni Z, Yang T, Zhang Y, Zeng Y, He J, Yang F, et al: Inhibition of COX2 enhances the chemosensitivity of dichloroacetate in cervical cancer cells. Oncotarget. 8:51748–51757. 2017.PubMed/NCBI
29	Chan MW, Wong CY, Cheng AS, Chan VY, Chan KK, To KF, Chan FK, Sung JJ and Leung WK: Targeted inhibition of COX-2 expression by RNA interference suppresses tumor growth and potentiates chemosensitivity to cisplatin in human gastric cancer cells. Oncol Rep. 18:1557–1562. 2007.PubMed/NCBI
30	Liu S, Zhang C, Zhang K, Gao Y, Wang Z, Li X, Cheng G, Wang S, Xue X, Li W, et al: FOXP3 inhibits cancer stem cell self-renewal via transcriptional repression of COX2 in colorectal cancer cells. Oncotarget. 8:44694–44704. 2017.PubMed/NCBI
31	Shimada K, Anai S, Marco DA, Fujimoto K and Konishi N: Cyclooxygenase 2-dependent and independent activation of Akt through casein kinase 2alpha contributes to human bladder cancer cell survival. BMC Urol. 11:82011. View Article : Google Scholar