Tumor Biology

, Volume 37, Issue 2, pp 2267–2273 | Cite as

Secreted protein acidic and rich in cysteine enhances the chemosensitivity of pancreatic cancer cells to gemcitabine

  • Xin Fan
  • Zhengfa Mao
  • Xiaoyan Ma
  • Lei Cui
  • Jianguo Qu
  • Lihui Lv
  • ShengChun Dang
  • Xuqing Wang
  • Jianxin ZhangEmail author
Original Article


It has been previously shown that the simultaneous exposure of colon cancer cells MIP to irinotecan and secreted protein acidic and rich in cysteine (SPARC) enhances anticancer activity. However, whether there is same effect of SPARC in pancreatic cancer remains largely unknown. Therefore in this study, we aimed to investigate the role of SPARC played in the sensitivity of pancreatic cancer to gemcitabine. We first treated MIAPaCa2 and MIAPaCa2/SPARC69 cells with different concentrations of gemcitabine (2, 5, 10, and 20 μM) for 24, 48, and 72 h and selected the appropriated concentration for further study. Then we analyzed cell viability, cell cycle, and apoptosis and the levels of apoptosis-related proteins by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, fluorescence-activated cell sorting and Western blot were used, respectively. In this study, we found that gemcitabine inhibited the proliferation of pancreatic cancer cells in a time- and dose-dependent manner. Overexpression of SPARC increased the inhibiting effect of gemcitabine on pancreatic cancer cells. The colony size of MIAPaCa2/SPARC69 was much smaller than that of MIAPaCa2/V. There was a G0/G1 arrest with significant increase of apoptosis after gemcitabine treatment in MIAPaCa2/SPARC69 cells. Furthermore, our results demonstrated that overexpression of SPARC markedly increased the levels of pro-apoptotic proteins in gemcitabine-treated pancreatic cancer cells. The SPARC can enhance the chemosensitivity of pancreatic cancer cells to gemcitabine via regulating the expression of apoptosis-related proteins. These results have shown that the SPARC/ gemcitabine combination treatment may be a potentially useful therapeutic option for individuals diagnosed with pancreatic cancer


Pancreatic cancer SPARC Gemcitabine Chemosensitivity 



The authors would like to thank Dr. Shi Lei (Chi Biotechnology) for critical reading. This work was sponsored by The natural science foundation of Jiangsu Province (Youth Fund), grant number BK20130475; Zhenjiang Science and Technology Pillar Program, grant numbers SH2012030, SH2012031, and SH2014035; The Foundation for Young Scientists of affiliated Hospital of Jiangsu University (grant number JDFYRC2013009); post-doctoral research funding schemes of Jiangsu Province (grant number 1302096B); and Research innovation project of Jiangsu Province General University Graduate (CXLX13-688).

Conflicts of interest



  1. 1.
    Hariharan D, Saied A, Kocher HM. Analysis of mortality rates for pancreatic cancer across the world. HPB (Oxford). 2008;10(1):58–62.CrossRefGoogle Scholar
  2. 2.
    Chang MC, Wong JM, Chang YT. Screening and early detection of pancreatic cancer in high risk population. World J Gastroenterol. 2014;20(9):2358–64.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Antoniou G, Kountourakis P, Papadimitriou K, Vassiliou V, Papamichael D. Adjuvant therapy for resectable pancreatic adenocarcinoma: review of the current treatment approaches and future directions. Cancer Treat Rev. 2014;40(1):78–85.CrossRefPubMedGoogle Scholar
  4. 4.
    Infante JR, Matsubayashi H, Sato N, Tonascia J, Klein AP, Riall TA, et al. Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. J Clin Oncol. 2007;25(3):319–25.CrossRefPubMedGoogle Scholar
  5. 5.
    Chen G, Tian X, Liu Z, Zhou S, Schmidt B, Henne-Bruns D, et al. Inhibition of endogenous SPARC enhances pancreatic cancer cell growth: modulation by FGFR1-III isoform expression. Br J Cancer. 2010;102(1):188–95.CrossRefPubMedGoogle Scholar
  6. 6.
    Zhang FX, Yang L, Li ZS, Zhang L, Gao J, Gong YF. SPARC gene expression in pancreatic cancer cell lines of its promoter methylation Ningxia. Med J. 2008;30(12):1087–8.Google Scholar
  7. 7.
    Sato N, Fukushima N, Maehara N, Matsubayashi H, Koopmann J, Su GH, et al. SPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor-stromal interactions. Oncogene. 2003;22(32):5021–30.CrossRefPubMedGoogle Scholar
  8. 8.
    Puolakkainen PA, Brekken RA, Muneer S, Sage EH. Enhanced growth of pancreatic tumors in SPARC-null mice is associated with decreased deposition of extracellular matrix and reduced tumor cell apoptosis. Mol Cancer Res. 2004;2(4):215–24.PubMedGoogle Scholar
  9. 9.
    Chen J, Wang M, Xi B, Xue J, He D, Zhang J, et al. SPARC is a key regulator of proliferation, apoptosis and invasion in human ovarian cancer. PLoS ONE. 2012;7(8):e42413.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Mason IJ, Taylor A, Williams JG, Sage H, Hogan BL. Evidence from molecular cloning that SPARC, a major product of mouse embryo parietal endoderm, is related to an endothelial cell ‘culture shock’ glycoprotein of Mr 43,000. EMBO J. 1986;5(7):1465–72.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Brekken RA, Sage EH. SPARC, a matricellular protein: at the crossroads of cell-matrix communication. Matrix Biol. 2001;19(8):816–27.CrossRefPubMedGoogle Scholar
  12. 12.
    Tai IT, Dai M, Owen DA, Chen LB. Genome-wide expression analysis of therapy-resistant tumors reveals SPARC as a novel target for cancer therapy. J Clin Invest. 2005;115(6):1492–502.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Saif MW. Pancreatic cancer: is this bleak landscape finally changing? Highlights from the ‘43rd ASCO Annual Meeting’. Chicago, IL, USA. June 1–5, 2007. JOP. 2007;8(4):365–73.PubMedGoogle Scholar
  14. 14.
    Fulda S, Debatin KM. Apoptosis signaling in tumor therapy. Ann N Y Acad Sci. 2004;1028:150–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Yang BF, Lu YJ, Wang ZG. MicroRNAs and apoptosis: implications in the molecular therapy of human disease. Clin Exp Pharmacol Physiol. 2009;36(10):951–60.CrossRefPubMedGoogle Scholar
  16. 16.
    Bast A, Krause K, Schmidt IH, Pudla M, Brakopp S, Hopf V, et al. Caspase-1-dependent and -independent cell death pathways in Burkholderia pseudomallei infection of macrophages. PLoS Pathog. 2014;10(3):e1003986.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Chan JM, Ho SH, Tai IT. Secreted protein acidic and rich in cysteine-induced cellular senescence in colorectal cancers in response to irinotecan is mediated by P53. Carcinogenesi. 2010;31(5):812–9.CrossRefGoogle Scholar
  18. 18.
    Mao Z, Ma X, Fa X, Cui L, Zhu T, Qu J, et al. Secreted protein acidic and rich in cysteine inhibits the growth of human pancreatic cancer cells with G1 arrest induction. Tumor Biol. 2014;35(10):10185–93.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Xin Fan
    • 1
  • Zhengfa Mao
    • 1
  • Xiaoyan Ma
    • 2
  • Lei Cui
    • 1
  • Jianguo Qu
    • 1
  • Lihui Lv
    • 3
  • ShengChun Dang
    • 1
  • Xuqing Wang
    • 1
  • Jianxin Zhang
    • 1
    Email author
  1. 1.Department of General SurgeryAffiliated Hospital of Jiangsu UniversityZhenjiangPeople’s Republic of China
  2. 2.Department of Gynecology and ObstetricsAffiliated Hospital of Jiangsu UniversityZhenjiangPeople’s Republic of China
  3. 3.Department of Senior officer’s Health CareNanjing General Hospital of Nanjing Military Area CommandNanjingPeople’s Republic of China

Personalised recommendations