Tumor Biology

, Volume 36, Issue 1, pp 303–313 | Cite as

Re-sensitization of 5-FU resistance by SPARC through negative regulation of glucose metabolism in hepatocellular carcinoma

  • Hong-Wei Hua
  • Feng Jiang
  • Qian Huang
  • Zhi-Jun Liao
  • Gang Ding
Research Article

Abstract

Secreted protein, acidic and rich in cysteine (SPARC), a calcium-binding matricellular glycoprotein, is implicated in the progression of many cancers. Currently, there is growing evidence for important functions of SPARC in a variety of cancers and its role in cancer depends on tumor types. In this study, we reported SPARC negatively regulated glucose metabolism in hepatocellular carcinoma (HCC). Overexpression of SPARC inhibited glucose uptake and lactate product through downregulation of key enzymes of glucose metabolism. On the other hand, knock down of SPARC reversed the phenotypes. Meanwhile, exogenous expression of SPARC in HepG2 cells resulted in tolerance to low glucose and was correlated with AMPK pathway. Interestingly, the 5-fluorouracil (5-FU)-resistant HepG2 cells showed increased glucose metabolism and downregulated SPARC levels. Finally, we reported the overexpression of SPARC re-sensitize 5-FU-resistant cells to 5-FU through inhibition of glycolysis both in vitro and in vivo. Our study proposed a novel function of SPARC in the regulation of glucose metabolism in hepatocellular carcinoma and will facilitate the development of therapeutic strategies for the treatments of liver tumor patients.

Keywords

SPARC 5-FU Glucose metabolism Hepatocellular carcinoma Re-sensitization 

Notes

Acknowledgments

This study was supported by Science and Technology Commission of Shanghai Municipality (12411960600), Key Project of Shanghai Municipal Commission of Health and Family Planning (ZK2012A06) and Talents Project of Shanghai Municipal Commission of Health and Family Planning (XBR2013089).

Conflicts of interest

None

References

  1. 1.
    Podhajcer OL, Benedetti LG, Girotti MR, Prada F, Salvatierra E, Llera AS. The role of the matricellular protein SPARC in the dynamic interaction between the tumor and the host. Cancer Metastasis Rev. 2008;27:691–705.CrossRefPubMedGoogle Scholar
  2. 2.
    Tai IT, Tang MJ. SPARC in cancer biology: its role in cancer progression and potential for therapy. Drug Resist Updat. 2008;11:231–46.CrossRefPubMedGoogle Scholar
  3. 3.
    Watkins G, Douglas-Jones A, Bryce R, Mansel RE, Jiang WG. Increased levels of SPARC (osteonectin) in human breast cancer tissues and its association with clinical outcomes. Prostaglandins Leukot Essent Fatty Acids. 2005;72:267–72.CrossRefPubMedGoogle Scholar
  4. 4.
    Azim HJ, Singhal S, Ignatiadis M, Desmedt C, Fumagalli D, Veys I. Association between SPARC mRNA expression, prognosis and response to neoadjuvant chemotherapy in early breast cancer: a pooled in-silico analysis. PLoS One. 2013;8:e62451.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Le Bail B, Faouzi S, Boussarie L, Guirouilh J, Blanc JF, Carles J, et al. Osteonectin/SPARC is overexpressed in human hepatocellular carcinoma. J Pathol. 1999;189:46–52.CrossRefPubMedGoogle Scholar
  6. 6.
    Derosa CA, Furusato B, Shaheduzzaman S, Srikantan V, Wang Z, Chen Y, et al. Elevated osteonectin/SPARC expression in primary prostate cancer predicts metastatic progression. Prostate Cancer Prostatic Dis. 2012;15:150–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Sansom OJ, Mansergh FC, Evans MJ, Wilkins JA, Clarke AR. Deficiency of SPARC suppresses intestinal tumorigenesis in APCMin/+mice. Gut. 2007;56:1410–4.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Girotti MR, Fernandez M, Lopez JA, Camafeita E, Fernandez EA, Albar JP, et al. SPARC promotes cathepsin B-mediated melanoma invasiveness through a collagen I/alpha2beta1 integrin axis. J Invest Dermatol. 2011;131:2438–47.CrossRefPubMedGoogle Scholar
  9. 9.
    Yunker CK, Golembieski W, Lemke N, Schultz CR, Cazacu S, Brodie C, et al. SPARC-induced increase in glioma matrix and decrease in vascularity are associated with reduced VEGF expression and secretion. Int J Cancer. 2008;122:2735–43.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Nagai MA, Gerhard R, Fregnani JH, Nonogaki S, Rierger RB, Netto MM, et al. Prognostic value of NDRG1 and SPARC protein expression in breast cancer patients. Breast Cancer Res Treat. 2011;126:1–14.CrossRefPubMedGoogle Scholar
  11. 11.
    Koblinski JE, Kaplan-Singer BR, VanOsdol SJ, Wu M, Engbring JA, Wang S, et al. Endogenous osteonectin/SPARC/BM-40 expression inhibits MDA-MB-231 breast cancer cell metastasis. Cancer Res. 2005;65:7370–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Atorrasagasti C, Malvicini M, Aquino JB, Alaniz L, Garcia M, Bolontrade M, et al. Overexpression of SPARC obliterates the in vivo tumorigenicity of human hepatocellular carcinoma cells. Int J Cancer. 2010;126:2726–40.PubMedGoogle Scholar
  13. 13.
    Said N, Frierson HJ, Chernauskas D, Conaway M, Motamed K, Theodorescu D. The role of SPARC in the TRAMP model of prostate carcinogenesis and progression. Oncogene. 2009;28:3487–98.CrossRefPubMedGoogle Scholar
  14. 14.
    Liang JF, Wang HK, Xiao H, Li N, Cheng CX, Zhao YZ, et al. Relationship and prognostic significance of SPARC and VEGF protein expression in colon cancer. J Exp Clin Cancer Res. 2010;29:71.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Yang B, Du Z, Bai T, Gao YT, Wang YJ, Lou C, et al. Aberrant methylation of SPARC in human hepatocellular carcinoma and its clinical implication. World J Gastroenterol. 2012;7:2043–52.Google Scholar
  16. 16.
    Zhu XC, Dong QZ, Zhang XF, Deng B, Jia HL, Ye QH, et al. Wu XZ: microRNA-29a suppresses cell proliferation by targeting SPARC in hepatocellular carcinoma. Int J Mol Med. 2012;30:1321–6.PubMedGoogle Scholar
  17. 17.
    Longley DB, Harkin DP, Johnston PG. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3:330–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Mirjolet JF, Barberi-Heyob M, Didelot C, Peyrat JP, Abecassis J, Millon R, et al. Bcl-2/Bax protein ratio predicts 5-fluorouracil sensitivity independently of p53 status. Br J Cancer. 2000;83:1380–6.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Zhu H, Guo W, Zhang L, Davis JJ, Teraishi F, Wu S, et al. Bcl-XL small interfering RNA suppresses the proliferation of 5-fluorouracil-resistant human colon cancer cells. Mol Cancer Ther. 2005;4:451–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Shi X, Liu S, Kleeff J, Friess H, Buchler MW. Acquired resistance of pancreatic cancer cells towards 5-Fluorouracil and gemcitabine is associated with altered expression of apoptosis-regulating genes. Oncology-Basel. 2002;62:354–62.CrossRefGoogle Scholar
  21. 21.
    Vander HM, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.CrossRefGoogle Scholar
  22. 22.
    Semenza GL. HIF-1 mediates the Warburg effect in clear cell renal carcinoma. J Bioenerg Biomembr. 2007;39:231–4.CrossRefPubMedGoogle Scholar
  23. 23.
    Hwang IT, Chung YM, Kim JJ, Chung JS, Kim BS, Kim HJ, et al. Drug resistance to 5-FU linked to reactive oxygen species modulator 1. Biochem Biophys Res Commun. 2007;359:304–10.CrossRefPubMedGoogle Scholar
  24. 24.
    Hakata T, Ito K, Horie T. Enhanced absorption of 3-O-methyl glucose following gastrointestinal injury induced by repeated oral administration of 5-FU in mice. J Pharm Sci. 2005;94:1713–22.CrossRefPubMedGoogle Scholar
  25. 25.
    Zhou Y, Tozzi F, Chen J, Fan F, Xia L, Wang J, et al. Intracellular ATP levels are a pivotal determinant of chemoresistance in colon cancer cells. Cancer Res. 2012;72:304–14.CrossRefPubMedGoogle Scholar
  26. 26.
    Hur H, Xuan Y, Kim YB, Lee G, Shim W, Yun J, et al. Expression of pyruvate dehydrogenase kinase-1 in gastric cancer as a potential therapeutic target. Int J Oncol. 2013;42:44–54.PubMedGoogle Scholar
  27. 27.
    Song H, Guan Y, Zhang L, Li K, Dong C. SPARC interacts with AMPK and regulates GLUT4 expression. Biochem Biophys Res Commun. 2010;396:961–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Said N, Frierson HF, Sanchez-Carbayo M, Brekken RA, Theodorescu D. Loss of SPARC in bladder cancer enhances carcinogenesis and progression. J Clin Invest. 2013;123:751–66.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Tang MJ, Tai IT. A novel interaction between procaspase 8 and SPARC enhances apoptosis and potentiates chemotherapy sensitivity in colorectal cancers. J Biol Chem. 2007;282:34457–67.CrossRefPubMedGoogle Scholar
  30. 30.
    Zhao Y, Butler EB, Tan M. Targeting cellular metabolism to improve cancer therapeutics. Cell Death Dis. 2013;4:e532.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004;64:3892–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Ding Y, Liu Z, Desai S, Zhao Y, Liu H, Pannell LK, et al. Receptor tyrosine kinase ErbB2 translocates into mitochondria and regulates cellular metabolism. Nat Commun. 2012;3:1271.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    White MK, Weber MJ. The src oncogene can regulate a human glucose transporter expressed in chicken embryo fibroblasts. Mol Cell Biol. 1990;10:1301–6.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Gaglio D, Metallo CM, Gameiro PA, Hiller K, Danna LS, Balestrieri C, et al. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol Syst Biol. 2011;7:523.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Madan E, Gogna R, Bhatt M, Pati U, Kuppusamy P, Mahdi AA. Regulation of glucose metabolism by p53: emerging new roles for the tumor suppressor. Oncotarget. 2011;2:948–57.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Blouin MJ, Zhao Y, Zakikhani M, Algire C, Piura E, Pollak M. Loss of function of PTEN alters the relationship between glucose concentration and cell proliferation, increases glycolysis, and sensitizes cells to 2-deoxyglucose. Cancer Lett. 2010;289:246–53.CrossRefPubMedGoogle Scholar
  37. 37.
    Shin YK, Yoo BC, Hong YS, Chang HJ, Jung KH, Jeong SY, et al. Upregulation of glycolytic enzymes in proteins secreted from human colon cancer cells with 5-fluorouracil resistance. Electrophoresis. 2009;30:2182–92.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Hong-Wei Hua
    • 1
  • Feng Jiang
    • 2
  • Qian Huang
    • 2
  • Zhi-Jun Liao
    • 2
  • Gang Ding
    • 1
    • 2
    • 3
  1. 1.Department of OncologyXin Hua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
  2. 2.Department of OncologyChongming Branch of Xinhua Hospital Shanghai Jiaotong University School of MedicineShanghaiChina
  3. 3.Institute of Cancer Pain transformationShanghaiChina

Personalised recommendations