Knockdown of MACC1 expression increases cisplatin sensitivity in cisplatin-resistant epithelial ovarian cancer cells

Zhang,Ruitao; Shi,Huirong; Ren,Fang; Li,Xia; Zhang,Minghui; Feng,Wei; Jia,Yanyan

doi:10.3892/or.2016.4585

Knockdown of MACC1 expression increases cisplatin sensitivity in cisplatin-resistant epithelial ovarian cancer cells

Authors:
- Ruitao Zhang
- Huirong Shi
- Fang Ren
- Xia Li
- Minghui Zhang
- Wei Feng
- Yanyan Jia
View Affiliations

Affiliations: Department of Gynaecology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
Published online on: January 21, 2016 https://doi.org/10.3892/or.2016.4585
Pages: 2466-2472

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

Abnormal expression of metastasis-associated in colon cancer 1 (MACC1) was found to be closely associated with several types of malignant tumors. The present study aimed to verify the relationship between MACC1 and cisplatin resistance in ovarian cancer cells and the possible mechanisms, which was implemented by inhibition of the expression of MACC1 in cisplatin-resistant human ovarian cancer cell lines A2780/DDP and COC1/DDP. MACC1 shRNA eukaryotic plasmids and negative control plasmids were transfected into A2780/DDP and COC1/DDP cells, respectively, while A2780/DDP and COC1/DDP cells were used as blank controls. Western blotting and sqRT-PCR were used to detect the expression of MACC1 in the different cell groups. Different concentrations of cispaltin (0, 10, 20, 30, 40, 50 and 60 µmol/l) were used to treat the cell groups, respectively, and then the chemosensitivity of cisplatin and cell apoptosis were examined by MTT and flow cytometry, respectively. The activity of caspase-3 was determined by spectrophotometry. Expression levels of p-ERK1/2, permeability glycoprotein (P-gp), B-cell lymphoma 2 (Bcl-2), Bcl-XL, Bax and Bad protein were detected in the different ovarian cancer cells by western blotting. After MACC1 knockdown, the chemosensitivity of cisplatin in the ovarian cancer cells was enhanced, and the cell growth inhibition and apoptosis rates were increased. The expression levels of Bax and Bad were upregulated, the activity of caspase-3 was increased, while the expression levels of p-ERK1/2, P-gp, Bcl-2 and Bcl-XL were downregulated as a result of MACC1 inhibition. These results indicate that inhibition of MACC1 improves the chemosensitivity of cisplatin in epithelial ovarian cancer cells, through the regulation of the ERK1/2 signaling pathway on P-gp and its downstream apoptosis proteins.

View Figures

View References

1	Ledermann JA and Kristeleit RS: Optimal treatment for relapsing ovarian cancer. Ann Oncol. 21(Suppl 7): vii218–vii222. 2010. View Article : Google Scholar : PubMed/NCBI
2	Schorge JO, Modesitt SC, Coleman RL, Cohn DE, Kauff ND, Duska LR and Herzog TJ: SGO White Paper on ovarian cancer: Etiology, screening and surveillance. Gynecol Oncol. 119:7–17. 2010. View Article : Google Scholar : PubMed/NCBI
3	Parmar MK, Ledermann JA, Colombo N, du Bois A, Delaloye JF, Kristensen GB, Wheeler S, Swart AM, Qian W, Torri V, et al ICON AGO Collaborators: Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: The ICON4/AGO-OVAR-2.2 trial. Lancet. 361:2099–2106. 2003. View Article : Google Scholar : PubMed/NCBI
4	Bookman MA: The addition of new drugs to standard therapy in the first-line treatment of ovarian cancer. Ann Oncol. 21(Suppl 7): vii211–vii217. 2010. View Article : Google Scholar : PubMed/NCBI
5	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
6	Shirahata A, Shinmura K, Kitamura Y, Sakuraba K, Yokomizo K, Goto T, Mizukami H, Saito M, Ishibashi K, Kigawa G, et al: MACC1 as a marker for advanced colorectal carcinoma. Anticancer Res. 30:2689–2692. 2010.PubMed/NCBI
7	Shirahata A, Sakata M, Kitamura Y, Sakuraba K, Yokomizo K, Goto T, Mizukami H, Saito M, Ishibashi K, Kigawa G, et al: MACC 1 as a marker for peritoneal-disseminated gastric carcinoma. Anticancer Res. 30:3441–3444. 2010.PubMed/NCBI
8	Shimokawa H, Uramoto H, Onitsuka T, Chundong G, Hanagiri T, Oyama T and Yasumoto K: Overexpression of MACC1 mRNA in lung adenocarcinoma is associated with postoperative recurrence. J Thorac Cardiovasc Surg. 141:895–898. 2011. View Article : Google Scholar
9	Shirahata A, Fan W, Sakuraba K, Yokomizo K, Goto T, Mizukami H, Saito M, Ishibashi K, Kigawa G, Nemoto H, et al: MACC 1 as a marker for vascular invasive hepatocellular carcinoma. Anticancer Res. 31:777–780. 2011.PubMed/NCBI
10	Zhang RT, Shi HR, Huang HL, Chen ZM, Liu HN and Yuan ZF: Expressions of MACC1, HGF, and C-met protein in epithelial ovarian cancer and their significance. Nan Fang Yi Ke Da Xue Xue Bao. 31:1551–1555. 2011.In Chinese. PubMed/NCBI
11	Wang G, Kang MX, Lu WJ, Chen Y, Zhang B and Wu YL: MACC1: A potential molecule associated with pancreatic cancer metastasis and chemoresistance. Oncol Lett. 4:783–791. 2012.PubMed/NCBI
12	Shang C, Hong Y, Guo Y, Liu YH and Xue YX: Influence of the MACC1 gene on sensitivity to chemotherapy in human U251 glioblastoma cells. Asian Pac J Cancer Prev. 16:195–199. 2015. View Article : Google Scholar : PubMed/NCBI
13	Zhang R, Shi H, Chen Z, Wu Q, Ren F and Huang H: Effects of metastasis-associated in colon cancer 1 inhibition by small hairpin RNA on ovarian carcinoma OVCAR-3 cells. J Exp Clin Cancer Res. 30:832011. View Article : Google Scholar : PubMed/NCBI
14	Chen S, Jiao JW, Sun KX, Zong ZH and Zhao Y: MicroRNA-133b targets glutathione S-transferase π expression to increase ovarian cancer cell sensitivity to chemotherapy drugs. Drug Des Devel Ther. 9:5225–5235. 2015.
15	Zhang Z, Xie Z, Sun G, Yang P, Li J, Yang H, Xiao S, Liu Y, Qiu H, Qin L, et al: Reversing drug resistance of cisplatin by hsp90 inhibitors in human ovarian cancer cells. Int J Clin Exp Med. 8:6687–6701. 2015.PubMed/NCBI
16	Li HF, Liu YQ, Shen ZJ, Gan XF, Han JJ, Liu YY, Li HG and Huang ZQ: Downregulation of MACC1 inhibits invasion, migration and proliferation, attenuates cisplatin resistance and induces apoptosis in tongue squamous cell carcinoma. Oncol Rep. 33:651–660. 2015.
17	Li H, Liao X, Liu Y, Shen Z, Gan X, Li H and Huang Z: The expression of MACC1 and its role in the proliferation and apoptosis of salivary adenoid cystic carcinoma. J Oral Pathol Med. 44:810–817. 2015. View Article : Google Scholar : PubMed/NCBI
18	Seger R and Krebs EG: The MAPK signaling cascade. FASEB J. 9:726–735. 1995.PubMed/NCBI
19	Nicosia SV, Bai W, Cheng JQ, Coppola D and Kruk PA: Oncogenic pathways implicated in ovarian epithelial cancer. Hematol Oncol Clin North Am. 17:927–943. 2003. View Article : Google Scholar : PubMed/NCBI
20	Jin W, Wu L, Liang K, Liu B, Lu Y and Fan Z: Roles of the PI-3K and MEK pathways in Ras-mediated chemoresistance in breast cancer cells. Br J Cancer. 89:185–191. 2003. View Article : Google Scholar : PubMed/NCBI
21	Montagut C and Settleman J: Targeting the RAF-MEK-ERK pathway in cancer therapy. Cancer Lett. 283:125–134. 2009. View Article : Google Scholar : PubMed/NCBI
22	Andorfer P and Rotheneder H: Regulation of the MDR1 promoter by E2F1 and EAPP. FEBS Lett. 587:1504–1509. 2013. View Article : Google Scholar : PubMed/NCBI
23	Chen J, Ding Z, Peng Y, Pan F, Li J, Zou L, Zhang Y and Liang H: HIF-1α inhibition reverses multidrug resistance in colon cancer cells via downregulation of MDR1/P-glycoprotein. PLoS One. 9:e988822014. View Article : Google Scholar
24	Wang Q, Wang Z, Chu L, Li X, Kan P, Xin X, Zhu Y and Yang P: The effects and molecular mechanisms of miR-106a in multidrug resistance reversal in human glioma U87/DDP and U251/G cell lines. PLoS One. 10:e01254732015. View Article : Google Scholar : PubMed/NCBI
25	Januchowski R, Wojtowicz K, Sujka-Kordowska P, Andrzejewska M and Zabel M: MDR gene expression analysis of six drug-resistant ovarian cancer cell lines. Biomed Res Int. 2013:2417632013. View Article : Google Scholar : PubMed/NCBI
26	Zhang T, Guan M, Jin HY and Lu Y: Reversal of multidrug resistance by small interfering double-stranded RNAs in ovarian cancer cells. Gynecol Oncol. 97:501–507. 2005. View Article : Google Scholar : PubMed/NCBI
27	Thomas S, Quinn BA, Das SK, Dash R, Emdad L, Dasgupta S, Wang XY, Dent P, Reed JC, Pellecchia M, et al: Targeting the Bcl-2 family for cancer therapy. Expert Opin Ther Targets. 17:61–75. 2013. View Article : Google Scholar
28	Babu A, Wang Q, Muralidharan R, Shanker M, Munshi A and Ramesh R: Chitosan coated polylactic acid nanoparticle-mediated combinatorial delivery of cisplatin and siRNA/Plasmid DNA chemosensitizes cisplatin-resistant human ovarian cancer cells. Mol Pharm. 11:2720–2733. 2014. View Article : Google Scholar : PubMed/NCBI
29	Yang HL, Lin KY, Juan YC, Kumar KJ, Way TD, Shen PC, Chen SC and Hseu YC: The anti-cancer activity of Antrodia camphorata against human ovarian carcinoma (SKOV-3) cells via modulation of HER-2/neu signaling pathway. J Ethnopharmacol. 148:254–265. 2013. View Article : Google Scholar : PubMed/NCBI
30	Galluzzi L, Kepp O and Kroemer G: Caspase-3 and prostaglandins signal for tumor regrowth in cancer therapy. Oncogene. 31:2805–2808. 2012. View Article : Google Scholar
31	Zhang SD, Shan L, Li W, Li HL and Zhang WD: Isochamaejasmin induces apoptosis in leukemia cells through inhibiting Bcl-2 family proteins. Chin J Nat Med. 13:660–666. 2015.PubMed/NCBI