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Butyrate inhibits pancreatic cancer invasion

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Journal of Gastrointestinal Surgery Aims and scope

Abstract

Pancreatic cancer is the most deadly gastrointestinal malignancy because of its propensity for local invasion and early metastasis. Integrin chains, in particular β4, can promote invasion in other cancers. The effect of sodium butyrate (NaBT), which induces differentiation in transformed cells, on integrin expression is unknown. The purpose of this study was to determine patterns of integrin expression in pancreatic cancer cells and investigate the effect of NaBT on integrin expression and invasion. Integrin expression was assessed in the less invasive MIA-PaCa-2 and PANC-1 and more invasive L3.6, AsPC-1, and SUIT-2 human pancreatic cancer cell lines by ribonuclease (RNase) protection assay. Western blotting and immunofluorescent staining for β4 expression was determined after NaBT treatment. Matrigel invasion chambers were used to assess pancreatic cancer cell invasion. β4 and β7 integrin expression was highest in L3.6, AsPC-1, and SUIT-2 cells. NaBT reduced the expression of β4 integrin in AsPC-1 cells including less cell surface β4. Invasion of AsPC-1 cells was also reduced by NaBT. Expression of β4 is higher in more aggressive pancreatic cancer cells; NaBT inhibits β4 expression and invasion. NaBT may represent a novel strategy to inhibit pancreatic cancer invasion and improve the prognosis of this deadly disease.

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References

  1. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin 2003;53:5–26.

    Article  PubMed  Google Scholar 

  2. Lillemoe KD, Yeo CJ, Cameron JL. Pancreatic cancer: State-of-the-art care. CA Cancer J Clin 2000;50:241–268.

    Article  PubMed  CAS  Google Scholar 

  3. Yeo CJ, Abrams RA, Grochow LB, Sohn TA, Ord SE, Hruban RH, Zahurak ML, Dooley WC, Coleman J, Sauter PK, Pitt HA, Lillemoe KD, Cameron JL. Pancreaticoduode-nectomy for pancreatic adenocarcinoma: Postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Ann Surg 1997;225:621–636.

    Article  PubMed  CAS  Google Scholar 

  4. Ellenrieder V, Adler G, Gress TM. Invasion and metastasis in pancreatic cancer. Ann Oncol 1999;10(Suppl 4):46–50.

    Article  PubMed  Google Scholar 

  5. Mercurio AM, Bachelder RE, Rabinovitz I, O’Connor KL, Tani T, Shaw LM. The metastatic odyssey: The integrin connection. Surg Oncol Clin North Am 2001;10:313–328, viii–ix.

    CAS  Google Scholar 

  6. Haas TA, Plow EF. Integrin-ligand interactions: A year in review. Curr Opin Cell Biol 1994;6:656–662.

    Article  PubMed  CAS  Google Scholar 

  7. Martin KH, Slack JK, Boerner SA, Martin CC, Parsons JT. Integrin connections map: To infinity and beyond. Science 2002;296:1652–1653.

    Article  PubMed  CAS  Google Scholar 

  8. Vogelmann R, Kreuser ED, Adler G, Lutz MP. Integrin alpha6beta1 role in metastatic behavior of human pancreatic carcinoma cells. Int J Cancer 1999;80:791–795.

    Article  PubMed  CAS  Google Scholar 

  9. Hosotani R, Kawaguchi M, Masui T, Koshiba T, Ida J, Fuji-moto K, Wada M, Doi R, Imamura M. Expression of integrin alphaVbeta3 in pancreatic carcinoma: Relation to MMP-2 activation and lymph node metastasis. Pancreas 2002;25:e30-e35.

    Article  PubMed  Google Scholar 

  10. Sawai H, Takeyama H, Yamamoto M, Furuta A, Funahashi H, Okada Y, Sato M, Tanaka M, Manabe T. Enhancement of integrins by interleukin-lalpha, and their relationship with metastatic and invasive behavior of human pancreatic ductal adenocarcinoma cells. J Surg Oncol 2003;82:51–56.

    Article  PubMed  CAS  Google Scholar 

  11. Litvak DA, Hwang KO, Evers BM, Townsend CM Jr. Induction of apoptosis in human gastric cancer by sodium butyrate. Anticancer Res 2000;20:779–784.

    PubMed  CAS  Google Scholar 

  12. Litvak DA, Evers BM, Hwang KO, Hellmich MR, Ko TC, Townsend CM Jr. Butyrate-induced differentiation of Caco-2 cells is associated with apoptosis and early induction of p21Waf1/Cip1 and p27Kip1. Surgery 1998;124:161–170.

    PubMed  CAS  Google Scholar 

  13. Zhang JS, Wang L, Huang H, Nelson M, Smith DI. Keratin 23 (K23), a novel acidic keratin, is highly induced by histone deacetylase inhibitors during differentiation of pancreatic cancer cells. Genes Chromosomes Cancer 2001;30:123–135.

    Article  PubMed  Google Scholar 

  14. Saito A, Yamashita T, Mariko Y, Nosaka Y, Tsuchiya K, Ando T, Suzuki T, Tsuruo T, Nakanishi O. A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc Natl Acad Sci U S A 1999;96:4592–4597.

    Article  PubMed  CAS  Google Scholar 

  15. Wang Q, Wang X, Hernandez A, Hellmich MR, Gatalica Z, Evers BM. Regulation of TRAIL expression by the phos-phatidylinositol 3-kinase/Akt/GSK-3 pathway in human colon cancer cells. J Biol Chem 2002;277:36602–36610.

    Article  PubMed  CAS  Google Scholar 

  16. Bruns CJ, Harbison MT, Kuniyasu H, Eue I, Fidler IJ. In vivo selection and characterization of metastatic variants from human pancreatic adenocarcinoma by using orthotopic implantation in nude mice. Neoplasia 1999;1:50–62.

    Article  PubMed  CAS  Google Scholar 

  17. Takamori H, Hiraoka T, Yamamoto T. Expression of tumor-associated carbohydrate antigens correlates with hepatic metastasis of pancreatic cancer: Clinical and experimental studies. Hepatogastroenterology 1996;43:748–755.

    PubMed  CAS  Google Scholar 

  18. Vincan E, Leet CS, Reyes NI, Dilley RJ, Thomas RJ, Phillips WA. Sodium butyrate-induced differentiation of human LIM253 7 colon cancer cells decreases GSK-3beta activity and increases levels of both membrane-bound and Apc/axin/GSK-3 beta complex-associated pools of beta-catenin. Oncol Res 2000;12:193–201.

    PubMed  CAS  Google Scholar 

  19. O’Connor KL, Shaw LM, Mercurio AM. Release of cAMP gating by the alpha6beta4 integrin stimulates lamellae formation and the chemotactic migration of invasive carcinoma cells. J Cell Biol 1998;143:1749–1760.

    Article  PubMed  CAS  Google Scholar 

  20. Gaetano C, Melchiori A, Albini A, Benelli R, Falcioni R, Modesti A, Modica A, Scarpa S, Sacchi A. Retinoic acid negatively regulates beta 4 integrin expression and suppresses the malignant phenotype in a Lewis lung carcinoma cell line. Clin Exp Metastasis 1994;12:63–72.

    Article  PubMed  CAS  Google Scholar 

  21. Shaw LM, Rabinovitz I, Wang HH, Toker A, Mercurio AM. Activation of phosphoinositide 3-OH kinase by the al-pha6beta4 integrin promotes carcinoma invasion. Cell 1997;91:949–960.

    Article  PubMed  CAS  Google Scholar 

  22. ChengJQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, Testa JR. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumor-igenicity by antisense RNA Proc Natl Acad Sci U S A 1996; 93:3636–3641.

    Article  PubMed  CAS  Google Scholar 

  23. Tanno S, Mitsuuchi Y, Altomare DA, Xiao GH, Testa JR. AKT activation upregulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells. Cancer Res 2001;61:589–593.

    PubMed  CAS  Google Scholar 

  24. Bergman EN. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol Rev 1990;70:567–590.

    PubMed  CAS  Google Scholar 

  25. Candido EP, Reeves R, Davie JR. Sodium butyrate inhibits histone deacetylation in cultured cells. Cell 1978;14:105–113.

    Article  PubMed  CAS  Google Scholar 

  26. Wang Q, Li N, Wang X, Kim MM, Evers BM. Augmentation of sodium butyrate-induced apoptosis by phosphatidylinositol 3′-kinase inhibition in the KM20 human colon cancer cell line. Clin Cancer Res 2002;8:1940–1947.

    PubMed  CAS  Google Scholar 

  27. Ellerhorst J, Nguyen T, Cooper DN, Estrov Y, Lotan D, Lotan R. Induction of differentiation and apoptosis in the prostate cancer cell line LNCaP by sodium butyrate and galectin-1. Int J Oncol 1999;14:225–232.

    PubMed  CAS  Google Scholar 

  28. Egawa N, Maillet B, VanDamme B, De Greve J, Kloppel G. Differentiation of pancreatic carcinoma induced by retinoic acid or sodium butyrate: A morphological and molecular analysis of four cell lines. Virchows Arch 1996;429:59–68.

    Article  PubMed  CAS  Google Scholar 

  29. Wang XM, Li J, Evers BM. Inhibition of proliferation, invasion and adhesion of liver cancer cells by 5-azacytidine and butyrate. Anticancer Res 1999;19:2901–2906.

    PubMed  CAS  Google Scholar 

  30. Dong-Le Bourhis X, Lambrecht V, Boilly B. Transforming growth factor beta 1 and sodium butyrate differentially modulate urokinase plasminogen activator and plasminogen activator inhibitor-1 in human breast normal and cancer cells. Br J Cancer 1998;77:396–403.

    Google Scholar 

  31. Steinert M, Wobus M, Boltze C, Schutz A, Wahlbuhl M, Hamann J, Aust G. Expression and regulation of CD97 in colorectal carcinoma cell lines and tumor tissues. Am J Pathol 2002;161:1657–1667.

    PubMed  CAS  Google Scholar 

  32. Berlin C, Berg EL, Briskin MJ, Andrew DP, Kilshaw PJ, Holzmann B, Weissman IL, Hamann A, Butcher EC. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular address in MAdCAM-1. Cell 1993;74:185–195.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to B. Mark Evers M.D..

Additional information

Supported by grants RO1 DK48498, PO1 DK35608, and T32 DK07639 from the National Institutes of Health. Dr. Farrow is the recipient of a Jeane B. Kempner award.

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Farrow, B., Rychahou, P., O’Connor, K.L. et al. Butyrate inhibits pancreatic cancer invasion. Journal of Gastrointestinal Surgery 7, 864–870 (2003). https://doi.org/10.1007/s11605-003-0031-y

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  • DOI: https://doi.org/10.1007/s11605-003-0031-y

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