Upregulation of miR-34a by diallyl disulfide suppresses invasion and induces apoptosis in SGC-7901 cells through inhibition of the PI3K/Akt signaling pathway

Wang,Guojun; Liu,Guanghui; Ye,Yanwei; Fu,Yang; Zhang,Xiefu

doi:10.3892/ol.2016.4266

Upregulation of miR-34a by diallyl disulfide suppresses invasion and induces apoptosis in SGC-7901 cells through inhibition of the PI3K/Akt signaling pathway

Authors:
- Guojun Wang
- Guanghui Liu
- Yanwei Ye
- Yang Fu
- Xiefu Zhang
View Affiliations

Affiliations: Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
Published online on: February 24, 2016 https://doi.org/10.3892/ol.2016.4266
Pages: 2661-2667

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

Diallyl disulfide (DADS) exerts anticarcinogenic activity in various types of cancer. However, the mechanism underlying its anticarcinogenic activity remains to be elucidated. The aim of the present study was to explore the mechanism of the anticarcinogenic activity of DADS in gastric cancer (GC). The expression levels of microRNA (miR)-34a in GC and normal tissues were measured using reverse transcription‑quantitative polymerase chain reaction (RT-qPCR). The expression of miR‑34a was also measured using RT-qPCR in SGC-7901 cells following treatment with DADS. In addition, the effect of DADS on the invasion capability of SGC‑7901 cells was observed in the presence of miR‑34a or anti‑miR‑34a using a Matrigel invasion assay. Furthermore, in identical conditions, the apoptosis of SGC‑7901 cells was observed using flow cytometry. Finally, the present study investigated the effects of DADS and miR‑34a on the phosphoinositide 3‑kinase (PI3K)/Akt signaling pathway in vitro. The level of miR‑34a in GC tissues was reduced compared with that in adjacent normal tissues (P<0.05). Treatment with DADS upregulated miR‑34a expression in SGC‑7901 cells (P<0.05). In the Matrigel invasion assay, DADS inhibited the invasive capability of SGC‑7901 cells (P<0.05 vs. control), which was improved by overexpression of miR‑34a (P<0.01 vs. control) but reduced by downregulation of miR‑34a (P<0.05 vs. DADS treatment group). Furthermore, DADS induced apoptosis of SGC‑7901 cells (P<0.05 vs. control); and DADS and miR‑34a synergistically enhanced apoptosis of SGC‑7901 cells (P<0.01 vs. control). In addition, DADS and miR‑34a inhibited the expression levels of phosphorylated (p)‑PI3K and p‑Akt (P<0.05 vs. control). By contrast, downregulation of miR‑34a alleviated the decrease in p‑PI3K and p‑Akt expression induced by DADS (P<0.05 vs. DADS treatment group). Cell viability was reduced with increasing concentrations of DADS, however, DADS did not affect cell viability following inhibition of the PI3K/Akt signaling pathway. In conclusion, DADS suppresses invasion and induces apoptosis of SGC-7901 cells by upregulation of miR-34a, via inhibition of the PI3K-Akt signaling pathway.

View Figures

View References

1	Cao W, Fan R, Wang L, Cheng S, Li H, Jiang J, Geng M, Jin Y and Wu Y: Expression and regulatory function of miRNA-34a in targeting survivin in gastric cancer cells. Tumor Biol. 34:963–971. 2013. View Article : Google Scholar
2	Xie B, Zhou J, Shu G, Liu DC, Zhou J, Chen J and Yuan L: Restoration of klotho gene expression induces apoptosis and autophagy in gastric cancer cells: Tumor suppressive role of klotho in gastric cancer. Cancer Cell Int. 13:182013. View Article : Google Scholar : PubMed/NCBI
3	Hartgrink HH, Jansen EP, van Grieken NC and van de Velde CJ: Gastric cancer. Lancet. 374:477–490. 2009. View Article : Google Scholar : PubMed/NCBI
4	Li Z, Wang Y, Dong S, Ge C, Xiao Y, Li R, Ma X, Xue Y, Zhang Q, Lv J, et al: Association of CXCR1 and 2 expressions with gastric cancer metastasis in ex vivo and tumor cell invasion in vitro. Cytokine. 69:6–13. 2014. View Article : Google Scholar : PubMed/NCBI
5	Yuan JP, Wang GH, Ling H, Su Q, Yang YH, Song Y, Tang RJ, Liu Y and Huang C: Diallyl disulfide-induced G2/M arrest of human gastric cancer MGC803 cells involves activation of p38 MAP kinase pathways. World J Gastroenterol. 10:2731–2734. 2004. View Article : Google Scholar : PubMed/NCBI
6	Zhang XD, Shu YQ, Liang J, Zhang FC, Ma XZ, Huang JJ, Chen L, Shi GM, Cao WG, Guo CY, et al: Combination chemotherapy with paclitaxel, cisplatin and fluorouracil for patients with advanced and metastatic gastric or esophagogastric junction adenocarcinoma: A multicenter prospective study. Chin J Cancer Res. 24:291–298. 2012. View Article : Google Scholar : PubMed/NCBI
7	Liu X, Liu Q, Fan Y, Wang S, Liu X, Zhu L, Liu M and Tang H: Downregulation of PPP2R5E expression by miR-23a suppresses apoptosis to facilitate the growth of gastric cancer cells. FEBS Lett. 588:3160–3169. 2014. View Article : Google Scholar : PubMed/NCBI
8	Xiao D, Lew KL, Kim YA, Zeng Y, Hahm ER, Dhir R and Singh SV: Diallyl trisulfide suppresses growth of PC-3 human prostate cancer xenograft in vivo in association with Bax and Bak induction. Clin Cancer Res. 12:6836–6843. 2006. View Article : Google Scholar : PubMed/NCBI
9	Lei XY, Yao SQ, Zu XY, Huang ZX, Liu LJ, Zhong M, Zhu BY, Tang SS and Liao DF: Apoptosis induced by diallyl disulfide in human breast cancer cell line MCF-7. Acta Pharmacol Sin. 29:1233–1239. 2008. View Article : Google Scholar : PubMed/NCBI
10	Robert V, Mouillé B, Mayeur C, Michaud M and Blachier F: Effects of the garlic compound diallyl disulfide on the metabolism, adherence and cell cycle of HT-29 colon carcinoma cells: Evidence of sensitive and resistant sub-populations. Carcinogenesis. 22:1155–1161. 2001. View Article : Google Scholar : PubMed/NCBI
11	Knowles LM and Milner JA: Diallyl disulfide induces ERK phosphorylation and alters gene expression profiles in human colon tumor cells. J Nutr. 133:2901–2906. 2003.PubMed/NCBI
12	Gunadharini DN, Arunkumar A, Krishnamoorthy G, Muthuvel R, Vijayababu MR, Kanagaraj P, Srinivasan N, Aruldhas MM and Arunakaran J: Antiproliferative effect of diallyl disulfide (DADS) on prostate cancer cell line LNCaP. Cell Biochem Funct. 24:407–412. 2006. View Article : Google Scholar : PubMed/NCBI
13	Wen J, Zhang Y, Chen X, Shen L, Li GC and Xu M: Enhancement of diallyl disulfide-induced apoptosis by inhibitors of MAPKs in human HepG2 hepatoma cells. Biochem Pharmacol. 68:323–331. 2004. View Article : Google Scholar : PubMed/NCBI
14	Tu F, Pan ZX, Yao Y, Liu HL, Liu SR, Xie Z and Li QF: miR-34a targets the inhibin β B gene, promoting granulosa cell apoptosis in the porcine ovary. Genet Mol Res. 13:2504–2512. 2014. View Article : Google Scholar : PubMed/NCBI
15	Forte E, Salinas RE, Chang C, Zhou T, Linnstaedt SD, Gottwein E, Jacobs C, Jima D, Li QJ, Dave SS and Luftig MA: The Epstein-Barr virus (EBV)-induced tumor suppressor microRNA MiR-34a is growth promoting in EBV-infected B cells. J Virol. 86:6889–6898. 2012. View Article : Google Scholar : PubMed/NCBI
16	Hwang HW and Mendell JT: MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer. 94:776–780. 2006. View Article : Google Scholar : PubMed/NCBI
17	Garzon R, Calin GA and Croce CM: MicroRNAs in cancer. Annu Rev Med. 60:167–179. 2009. View Article : Google Scholar : PubMed/NCBI
18	Di Leva G, Garofalo M and Croce CM: MicroRNAs in cancer. Annu Rev Pathol. 9:287–314. 2014. View Article : Google Scholar : PubMed/NCBI
19	Ueda T, Volinia S, Okumura H, Shimizu M, Taccioli C, Rossi S, Alder H, Liu CG, Oue N, Yasui W, et al: Relation between microRNA expression and progression and prognosis of gastric cancer: A microRNA expression analysis. Lancet Oncol. 11:136–146. 2010. View Article : Google Scholar : PubMed/NCBI
20	Guo J, Miao Y, Xiao B, Huan R, Jiang Z, Meng D and Wang Y: Differential expression of microRNA species in human gastric cancer versus non-tumorous tissues. J Gastroenterol Hepatol. 24:652–657. 2009. View Article : Google Scholar : PubMed/NCBI
21	Liu R, Zhang C, Hu Z, Li G, Wang C, Yang C, Huang D, Chen X, Zhang H, Zhuang R, et al: A five-microRNA signature identified from genome-wide serum microRNA expression profiling serves as a fingerprint for gastric cancer diagnosis. Eur J Cancer. 47:784–791. 2011. View Article : Google Scholar : PubMed/NCBI
22	Livak and Schmittgen: Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCt method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
23	McManus MT: MicroRNAs and cancer. Semin Cancer Biol. 13:253–258. 2003. View Article : Google Scholar : PubMed/NCBI
24	Li X, Zhang Y, Zhang H, Liu X, Gong T, Li M, Sun L, Ji G, Shi Y, Han Z, et al: miRNA-223 promotes gastric cancer invasion and metastasis by targeting tumor suppressor EPB41L3. Mol Cancer Res. 9:824–833. 2011. View Article : Google Scholar : PubMed/NCBI
25	Ambros V: MicroRNA pathways in flies and worms: Growth, death, fat, stress, and timing. Cell. 113:673–676. 2003. View Article : Google Scholar : PubMed/NCBI
26	Zhang BG, Li JF, Yu BQ, Zhu ZG, Liu BY and Yan M: microRNA-21 promotes tumor proliferation and invasion in gastric cancer by targeting PTEN. Oncol Rep. 27:1019–1026. 2012.PubMed/NCBI
27	Tang H, Kong Y, Guo J, Tang Y and Xie X, Yang L, Su Q and Xie X: Diallyl disulfide suppresses proliferation and induces apoptosis in human gastric cancer through Wnt-1 signaling pathway by up-regulation of miR-200b and miR-22. Cancer Lett. 340:72–81. 2013. View Article : Google Scholar : PubMed/NCBI
28	Cho WJ, Shin JM, Kim JS, Lee MR, Hong KS, Lee JH, Koo KH, Park JW and Kim KS: miR-372 regulates cell cycle and apoptosis of ags human gastric cancer cell line through direct regulation of LATS2. Mol Cells. 28:521–527. 2009. View Article : Google Scholar : PubMed/NCBI
29	Luo J, Manning BD and Cantley LC: Targeting the PI3K-Akt pathway in human cancer: Rationale and promise. Cancer Cell. 4:257–262. 2003. View Article : Google Scholar : PubMed/NCBI
30	West KA, Castillo SS and Dennis PA: Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist Updat. 5:234–248. 2002. View Article : Google Scholar : PubMed/NCBI
31	Vivanco I and Sawyers CL: The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2:489–501. 2002. View Article : Google Scholar : PubMed/NCBI
32	Vara Fresno JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C and González-Barón M: PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 30:193–204. 2004. View Article : Google Scholar : PubMed/NCBI
33	Kang MH, Oh SC, Lee HJ, Kang HN, Kim JL, Kim JS and Yoo YA: Metastatic function of BMP-2 in gastric cancer cells: The role of PI3K/AKT, MAPK, the NF-κB pathway and MMP-9 expression. Exp Cell Res. 317:1746–1762. 2011. View Article : Google Scholar : PubMed/NCBI
34	Yun SM: Abstract 4304: PPP1R1B-STARD3 fusion gene promotes gastric tumorigenesis through activation of PI3K/Akt signaling. Cancer Res. 73:43042013. View Article : Google Scholar
35	Shrivastava S, Jeengar MK, Thummuri D and Naidu VGM: P1 Piperlongumine inhibits growth potential of gastric cancer cells by targeting PI3K/Akt/mTOR signaling pathway. Eur J Cancer. 50:S92014. View Article : Google Scholar
36	Lee IC, Kim SH, Baek HS, Beak HS, Moon C, Kim SH, Kim YB, Yun WK, Kim HC and Kim JC: Protective effects of diallyl disulfide on carbon tetrachloride-induced hepatotoxicity through activation of Nrf2. Environ Toxicol. 30:538–548. 2015. View Article : Google Scholar : PubMed/NCBI
37	Takahashi S, Hakoi K, Yada H, Hirose M, Ito N and Fukushima S: Enhancing effects of diallyl sulfide on hepatocarcinogenesis and inhibitory actions of the related diallyl disulfide on colon and renal carcinogenesis in rats. Carcinogenesis. 13:1513–1518. 1992. View Article : Google Scholar : PubMed/NCBI
38	Druesne N, Pagniez A, Mayeur C, Thomas M, Cherbuy C, Duée PH, Martel P and Chaumontet C: Diallyl disulfide (DADS) increases histone acetylation and p21(waf1/cip1) expression in human colon tumor cell lines. Carcinogenesis. 25:1227–1236. 2004. View Article : Google Scholar : PubMed/NCBI