Silencing XIAP suppresses osteosarcoma cell growth,
and enhances the sensitivity of osteosarcoma cells
to doxorubicin and cisplatin Retraction in /10.3892/or.2021.8213

Qu,Yang; Xia,Peng; Zhang,Shanyong; Pan,Su; Zhao,Jianwu

doi:10.3892/or.2014.3698

Silencing XIAP suppresses osteosarcoma cell growth, and enhances the sensitivity of osteosarcoma cells to doxorubicin and cisplatin

Retraction in: /10.3892/or.2021.8213

Authors:
- Yang Qu
- Peng Xia
- Shanyong Zhang
- Su Pan
- Jianwu Zhao
View Affiliations

Affiliations: Department of Orthopedics, The Second Hospital of Jilin University, Nanguan, Changchun, Jilin 130042, P.R. China
Published online on: December 23, 2014 https://doi.org/10.3892/or.2014.3698
Pages: 1177-1184

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

X-chromosome-linked inhibitor of apoptosis protein (XIAP) is an important member of the inhibitors of apoptosis (IAP) family. It has been shown that XIAP promotes the invasion, metastasis, growth and survival of malignant cells, and confers resistance to some chemotherapeutic drugs in various types of cancer. However, little is known regarding its detailed role in osteosarcoma (OS). In the present study, we first investigated the expression of XIAP in OS tissues, and an increased expression of XIAP in OS tissues compared to adjacent non-tumor tissue was identified. Additionally, its expression level correlated with key pathological characteristics including clinical stage, tumor size and metastasis. Subsequently, small interfering RNA (siRNA) was used to block XIAP expression to evaluate the effect of XIAP siRNA on cell proliferation, colony formation, cell cycle, apoptosis, tumorigenicity, and the combined effects of doxorubicin or cisplatin in OS cell lines (MG63 cells). Downregulation of XIAP expression using the RNA silencing approach efficiently decreased cell proliferation and colony formation, and induced cell apoptosis and cell cycle in the G0/G1 stage. In addition, this downregulation inhibited tumor growth in a nude murine model. The resuls also showed that treatment with XIAP-shRNA in combination with doxorubicin or cisplatin enhanced chemosensitivity. These results suggested that XIAP may aid the diagnosis of OS and may be an effective strategy for gene therapy of this disease.

View Figures

View References

1	Ottaviani G, Robert RS, Huh WW, Palla S and Jaffe N: Sociooccupational and physical outcomes more than 20 years after the diagnosis of osteosarcoma in children and adolescents: limb salvage versus amputation. Cancer. 119:3727–3736. 2013.PubMed/NCBI
2	Ottaviani G and Jaffe N: The epidemiology of osteosarcoma. Cancer Treat Res. 152:3–13. 2009. View Article : Google Scholar
3	Wittig JC, Bickels J, Priebat D, et al: Osteosarcoma: a multidisciplinary approach to diagnosis and treatment. Am Fam Physician. 65:1123–1132. 2002.PubMed/NCBI
4	Meyers PA, Schwartz CL, Krailo M, et al: Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol. 23:2004–2011. 2005. View Article : Google Scholar : PubMed/NCBI
5	Yang J and Zhang W: New molecular insights into osteosarcoma targeted therapy. Curr Opin Oncol. 25:398–406. 2013. View Article : Google Scholar : PubMed/NCBI
6	Zhao Z, Tao L, Shen C, Liu B, Yang Z and Tao H: Silencing of Barkor/ATG14 sensitizes osteosarcoma cells to cisplatin-induced apoptosis. Int J Mol Med. 33:271–276. 2014.
7	Mobahat M, Narendran A and Riabowol K: Survivin as a preferential target for cancer therapy. Int J Mol Sci. 15:2494–2516. 2014. View Article : Google Scholar : PubMed/NCBI
8	Wang S, Bai L, Lu J, Liu L, Yang CY and Sun H: Targeting inhibitors of apoptosis proteins (IAPs) for new breast cancer therapeutics. J Mammary Gland Biol Neoplasia. 17:217–228. 2012. View Article : Google Scholar : PubMed/NCBI
9	Salvesen GS and Duckett CS: IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol. 3:401–410. 2002. View Article : Google Scholar : PubMed/NCBI
10	Devi GR: XIAP as target for therapeutic apoptosis in prostate cancer. Drug News Perspect. 17:127–134. 2004. View Article : Google Scholar : PubMed/NCBI
11	Stennicke HR, Ryan CA and Salvesen GS: Reprieval from execution: the molecular basis of caspase inhibition. Trends Biochem Sci. 27:94–101. 2002. View Article : Google Scholar : PubMed/NCBI
12	Holcik M, Gibson H and Korneluk RG: XIAP: apoptotic brake and promising therapeutic target. Apoptosis. 6:253–261. 2001. View Article : Google Scholar : PubMed/NCBI
13	Ma JJ, Chen BL and Xin XY: XIAP gene downregulation by small interfering RNA inhibits proliferation, induces apoptosis, and reverses the cisplatin resistance of ovarian carcinoma. Eur J Obstet Gynecol Reprod Biol. 146:222–226. 2009. View Article : Google Scholar : PubMed/NCBI
14	Yamaguchi Y, Shiraki K, Fuke H, et al: Targeting of X-linked inhibitor of apoptosis protein or survivin by short interfering RNAs sensitize hepatoma cells to TNF-related apoptosis-inducing ligand- and chemotherapeutic agent-induced cell death. Oncol Rep. 14:1311–1316. 2005.PubMed/NCBI
15	Jiang C, Yi XP, Shen H and Li YX: Targeting X-linked inhibitor of apoptosis protein inhibits pancreatic cancer cell growth through p-Akt depletion. World J Gastroenterol. 18:2956–2965. 2012. View Article : Google Scholar : PubMed/NCBI
16	Kwatra SG: Targeting x-linked inhibitor of apoptosis protein for melanoma therapy: the need for more homogeneous samples and the importance of cell lines. J Invest Dermatol. 131:7972011. View Article : Google Scholar
17	Hiscutt EL, Hill DS, Martin S, et al: Targeting X-linked inhibitor of apoptosis protein to increase the efficacy of endoplasmic reticulum stress-induced apoptosis for melanoma therapy. J Invest Dermatol. 130:2250–2258. 2010. View Article : Google Scholar : PubMed/NCBI
18	Mastrangelo E, Cossu F, Milani M, et al: Targeting the X-linked inhibitor of apoptosis protein through 4-substituted azabicyclo[5.3.0]alkane smac mimetics. Structure, activity, and recognition principles. J Mol Biol. 384:673–689. 2008. View Article : Google Scholar : PubMed/NCBI
19	Harlin H, Reffey SB, Duckett CS, Lindsten T and Thompson CB: Characterization of XIAP-deficient mice. Mol Cell Biol. 21:3604–3608. 2001. View Article : Google Scholar : PubMed/NCBI
20	Deveraux QL and Reed JC: IAP family proteins - suppressors of apoptosis. Genes Dev. 13:239–252. 1999. View Article : Google Scholar : PubMed/NCBI
21	Cheng JQ, Jiang X, Fraser M, et al: Role of X-linked inhibitor of apoptosis protein in chemoresistance in ovarian cancer: possible involvement of the phosphoinositide-3 kinase/Akt pathway. Drug Resist Updat. 5:131–146. 2002. View Article : Google Scholar : PubMed/NCBI
22	Gagnon V, Van Themsche C, Turner S, Leblanc V and Asselin E: Akt and XIAP regulate the sensitivity of human uterine cancer cells to cisplatin, doxorubicin and taxol. Apoptosis. 13:259–271. 2008. View Article : Google Scholar
23	Holt SV, Brookes KE, Dive C and Makin GW: Down-regulation of XIAP by AEG35156 in paediatric tumour cells induces apoptosis and sensitises cells to cytotoxic agents. Oncol Rep. 25:1177–1181. 2011.PubMed/NCBI
24	Zhang Y, Wang Y, Gao W, et al: Transfer of siRNA against XIAP induces apoptosis and reduces tumor cells growth potential in human breast cancer in vitro and in vivo. Breast Cancer Res Treat. 96:267–277. 2006. View Article : Google Scholar
25	Oberoi-Khanuja TK, Murali A and Rajalingam K: IAPs on the move: role of inhibitors of apoptosis proteins in cell migration. Cell Death Dis. 4:e7842013. View Article : Google Scholar : PubMed/NCBI
26	Hunter AM, LaCasse EC and Korneluk RG: The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis. 12:1543–1568. 2007. View Article : Google Scholar : PubMed/NCBI
27	Berthelet J and Dubrez L: Regulation of apoptosis by inhibitors of apoptosis (IAPs). Cells. 2:163–187. 2013. View Article : Google Scholar : PubMed/NCBI
28	Schimmer AD: Inhibitor of apoptosis proteins: translating basic knowledge into clinical practice. Cancer Res. 64:7183–7190. 2004. View Article : Google Scholar : PubMed/NCBI
29	Carter BZ, Kornblau SM, Tsao T, et al: Caspase-independent cell death in AML: caspase inhibition in vitro with pan-caspase inhibitors or in vivo by XIAP or Survivin does not affect cell survival or prognosis. Blood. 102:4179–4186. 2003. View Article : Google Scholar : PubMed/NCBI
30	Abe S, Nishimoto Y, Isu K, Ishii T and Goto T; Japanese Musculoskeletal Oncology G. Preoperative cisplatin for initial treatment of limb osteosarcoma: its local effect and impact on prognosis. Cancer Chemother Pharmacol. 50:320–324. 2002. View Article : Google Scholar : PubMed/NCBI
31	Anninga JK, Gelderblom H, Fiocco M, et al: Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand? Eur J Cancer. 47:2431–2445. 2011. View Article : Google Scholar : PubMed/NCBI
32	Chou AJ and Gorlick R: Chemotherapy resistance in osteosarcoma: current challenges and future directions. Expert Rev Anticancer Ther. 6:1075–1085. 2006. View Article : Google Scholar : PubMed/NCBI
33	Li J, Feng Q, Kim JM, et al: Human ovarian cancer and cisplatin resistance: possible role of inhibitor of apoptosis proteins. Endocrinology. 142:370–380. 2001.PubMed/NCBI
34	Miyamoto M, Takano M, Iwaya K, et al: X-chromosome-linked inhibitor of apoptosis as a key factor for chemoresistance in clear cell carcinoma of the ovary. Br J Cancer. 110:2881–2886. 2014. View Article : Google Scholar : PubMed/NCBI
35	Cheng YJ, Jiang HS, Hsu SL, et al: XIAP-mediated protection of H460 lung cancer cells against cisplatin. Eur J Pharmacol. 627:75–84. 2010. View Article : Google Scholar
36	Weiss RB: The anthracyclines: will we ever find a better doxorubicin? Semin Oncol. 19:670–686. 1992.PubMed/NCBI
37	Carvalho C, Santos RX, Cardoso S, et al: Doxorubicin: the good, the bad and the ugly effect. Curr Med Chem. 16:3267–3285. 2009. View Article : Google Scholar : PubMed/NCBI
38	Nobuto H, Sugita T, Kubo T, et al: Evaluation of systemic chemotherapy with magnetic liposomal doxorubicin and a dipole external electromagnet. Int J Cancer. 109:627–635. 2004. View Article : Google Scholar : PubMed/NCBI