Connective tissue growth factor reacts as an IL - World Journal of ...

More documents

Recommendations

Info

A Tumor volume (mm 3 ) C 5000 4000 3000 2000 1000 0 Phospho-AktSer 473 NFκB-p65 FasL Active caspase-8 t-Bid c-FLIPS Active caspase-3 Control LY294002 Oxaliplatin Oxaliplatin + LY294002 0 1 2 3 4 5 6 7 t /wk FAK Phospho-AktSer 473 NFκB-p65 Control LY294002 Oxaliplatin Oxaliplatin + LY294002 WJG|www.wjgnet.com B HE TUNEL Liu J et al . LY294002 and oxaliplatin inhibit tumor growth Control LY294002 Oxaliplatin Oxaliplatin + LY294002 Figure 5 Effects of oxaliplatin, LY294002, or combination on in vivo tumor growth and apoptosis. A: Tumor volumes of nude mice in each group are presented. Each time point represents the mean tumor volume for each group; B: Detection of apoptotic cells in tumor tissue was performed by transferase-mediated dUTP nick end labeling (TUNEL) assay; C: The expression of phospho-AktSer 473 , nuclear factor κB (NFκB)-p65, Fas ligand (FasL), short form of cellular caspase-8/FLICEinhibitory protein (c-FLIPS), Bid, caspase-8, and caspase-3 was investigated by immunohistochemical analysis. 187 January 14, 2011|Volume 17|Issue 2|
Liu J et al . LY294002 and oxaliplatin inhibit tumor growth blocked basal and oxaliplatin-induced phosphorylation of Akt, and resulted in an increased apoptotic rate compared with oxaliplatin alone, suggesting that Akt phosphorylation might regulate oxaliplatin resistance in gastric cancer cells. The significant increase in oxaliplatin-induced cytotoxicity in gastric cancer pretreated with LY294002 indicates that the resistance of gastric cancer cells to chemotherapeutic agents can be modulated. NFκB plays an important role in suppression of apoptosis. Akt phosphorylates IκB (NFκB inhibitor) kinases, leading to degradation of IκB, as well as NFκB activation [34] . Although many studies strongly support the antiapoptotic role of NFκB, there are some evidences that NFκB can induce apoptosis [35-37] . In the present study, oxaliplatin enhanced NFκB/DNA binding activity, while LY294002 blocked anticancer drug-induced activation of NFκB. These data indicate that activation of Akt/NFκB in gastric cancer cells may be a key mechanism in inhibiting oxaliplatin-induced apoptosis. It is possible that additional components of the PI3K/Akt pathway may be involved in the chemoresistance of gastric cancer cells. To further define the role of LY294002 in the regulation of oxaliplatin-induced apoptosis, we examined expression of molecular markers of the death receptor-signaling pathway. LY294002 dramatically increased oxaliplatininduced FasL expression, FADD redistribution into membrane lipid rafts, caspase-8 and caspase-3 activation, and Bid cleavage in MKN45 and AGS cells. Next, we downregulated FasL using FasL siRNA in LY294002-, oxaliplatin-, or combination-treated MKN45 and AGS cells. Oxaliplatin, LY294002, or combination treatment-induced apoptosis was attenuated by FasL silencing, suggesting that the death receptor pathway might be involved in the cell apoptosis induced by oxaliplatin or LY294002 in gastric cancer cells. However, the precise mechanism whereby oxaliplatin or LY294002 induces FasL expression remains unknown. Apoptosis mediated by Fas is regulated by c-FLIP expression [38] . There are two isoforms of c-FLIP: the fulllength c-FLIPL and c-FLIPS [39,40] . c-FLIPS is considered solely anti-apoptotic and confers resistance to receptormediated apoptosis by blocking proteolytic activation of caspase-8 at the Fas DISC, while c-FLIPL exhibits dual roles [41,42] . Additionally, c-FLIPS and c-FLIPL are differently regulated [43-45] . The PI3K pathway is an important regulator of c-FLIPS, but not c-FLIPL, expression in human gastric cancer cells [45] . In this study, oxaliplatininduced apoptotic death was accompanied by suppression of c-FLIPS in MKN45 and AGS cells. Compared with oxaliplatin alone, combination of oxaliplatin and LY294002 produced enhanced down-regulation of c-FLIPS. c-FLIPL expression was not significantly changed by treatment with LY294002 or oxaliplatin. These findings indicate that the anti-apoptotic function of c-FLIPS may be more potent than that of c-FLIPL in oxaliplatin-induced apoptosis, and that Akt is involved in regulation of c-FLIPS in human gastric cancer cells. We also examined the effects of the combined treatment of oxaliplatin and LY294002 in an in vivo xeno- WJG|www.wjgnet.com graft model. LY29400 significantly increased oxaliplatininduced tumor growth and cell death in the tumor mass via apoptosis. Moreover, altered expression levels of FasL, Bid, caspase-8, caspase-3, and c-FLIPS were found in the tumor xenograft. These data suggest that combination of oxaliplatin and LY294002 elicited a strong antitumor effect in gastric cancer in vivo, and that the death receptor pathway might mediate the additive cytotoxicity of oxaliplatin and LY294002. In summary, we present a novel therapeutic approach for treatment of gastric cancer using the combined oxaliplatin and the PI3K/Akt inhibitor LY294002, that may be mediated, at least in part, by modification of the death receptor pathway. ACKNOWLEDGMENTS The authors thank Hong Xia (Institute for Gastroenterology and Hepatology, Wuhan University Medical School) for his valuable discussions and suggestions. COMMENTS Background Gastric cancer remains a leading cause of cancer death worldwide. Besides surgical resection, chemotherapy is important treatment for gastric cancers. Despite the improvement in the efficacy of chemotherapeutic drugs, the response rates and the median survival remain low. Research frontiers Traditional cancer therapy predominantly utilizes cytotoxic chemotherapeutic agents. The cytotoxic events are affected mainly through disruption of various aspects of DNA synthesis and repair or disturbance of mitosis, processes which are common to all dividing cells. For this reason, most chemotherapeutic agents are often accompanied with substantial adverse effects. Target-protein-based cancer therapy has become available in clinical practice. Phosphatidylinositol 3’-kinase (PI3K) inhibitors have potential to target specific pathways involved in tumor cell growth. Innovations and breakthroughs The PI3K/Akt pathway has been shown to be involved in the chemoresistance of gastric cancer. In both in vitro and in vivo studies, the targeted inhibition of PI3K/Akt results in increased oxaliplatin-induced apoptosis and inhibition of cellular proliferation of gastric cancer. Furthermore, the activation of the death receptor pathway may be an important mechanism by which PI3K/Akt inhibition is involved in oxaliplatin-induced apoptosis. Applications By understanding how LY294002 enhances the therapeutic effect of oxaliplatin in gastric cancer cells, this study provides information about the potential therapeutic intervention in patients with gastric adenocarcinoma. Terminology Oxaliplatin: A third-generation platinum coordination complex of the 1,2-diaminocyclohexane families, generates covalent adducts between platinum and two adjacent guanines or guanine and adenine in cell DNA. LY294002: 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, a specific inhibitor of PI3K. Peer review This is a well-written report on the synergistic anti-tumor effects of the combined treatment with oxaliplatin and LY294002 in gastric cancer cells. The data and results are straight-forward and clearly support the conclusion that targeting PI3K/Akt results in increased oxaliplatin-induced apoptosis and inhibition of cellular proliferation of gastric cancer. REFERENCES 1 Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55: 74-108 188 January 14, 2011|Volume 17|Issue 2|
Page 1 and 2:
World Journal of Gastroenterology W
Page 3 and 4:
Robert JL Fraser, Daw Park Jacob Ge
Page 5 and 6:
Italy Donato F Altomare, Bari Piero
Page 7 and 8:
Fernando Azpiroz, Barcelona Ramon B
Page 9 and 10:
S Contents EDITORIAL TOPIC HIGHLIGH
Page 11 and 12: Contents APPENDIX FLYLEAF EDITORS F
Page 13 and 14: Ouyang D et al . Pancreatic endocri
Page 19 and 20: Online Submissions: http://www.wjgn
Page 21 and 22: Diamantis G et al . Quality of life
Page 27: Gressner OA et al . CTGF is a negat
Page 30 and 31: A B CTGF luciferase activity (lcps)
Page 32 and 33: A B IL-6 (35 μg/L) - - + + + + - s
Page 34 and 35: F mt distal mt proximal wt 9 8 7 6
Page 36 and 37: + CTGF TGF-β IL-6 + - + an acute p
Page 38 and 39: 2007; 46: 295-303 21 Karger A, Fitz
Page 40 and 41: 2011; 17(2): 164-173 Available from
Page 43 and 44: A B C -80 mV E Relative expression
Page 45: A C Park KS et al . Serotonergic si
Page 48 and 49: 19 Li T, Weng SG, Leng XS, Peng JR,
Page 50 and 51: Recurrent GB cancer has been report
Page 52 and 53: Table 2 Surgical procedures for muc
Page 54 and 55: esection of the common bile duct sh
Page 58 and 59: NaF, 1% Triton X-100, and 0.5 mmol/
Page 60 and 61: A Oxaliplatin LY294002 C Oxaliplati
Page 64 and 65: 2 Hundahl SA, Phillips JL, Menck HR
Page 68 and 69: the typical MII pattern of GOR. Thi
Page 70 and 71: emptying, that arises from the anch
Page 74 and 75: medical treatment, age at diagnosis
Page 76 and 77: Table 3 Odds ratio for the studied
Page 78 and 79: Table 6 Published associations betw
Page 80 and 81: anti-CBir1 and ASCA, and show reduc
Page 85: Faria GR et al . Acute diverticulit
Page 90 and 91: Changes in flow vs T0 (%) Changes i
Page 93 and 94: Hanssen SJ et al . Hemolysis and in
Page 95 and 96: Kuiper P et al . Angiogenic markers
Page 97 and 98: Kuiper P et al . Angiogenic markers
Page 99 and 100: A Comulative survival C Comulative
Page 103 and 104: Nishida U et al . ASA induced small
Page 105 and 106: Nishida U et al . ASA induced small
Page 107 and 108: Okano K et al . FDG-PET small pancr
Page 109 and 110: Okano K et al . FDG-PET small pancr
Page 111: Online Submissions: http://www.wjgn
Page 114 and 115:
Table 3 Prevalence of IgG anti-hepa
Page 116:
1005-1022 24 Hendrickx G, Van Herck
Page 123:
Choi YS et al . Alternative cleansi
Page 129 and 130:
Online Submissions: http://www.wjgn
Page 131 and 132:
Plasma endotoxin (EU/L) Small intes
Page 133 and 134:
Zhang Y et al . Effects of penehycl
Page 135:
Page 139:
C Review: CYP1A1 Ile462Val polymorp
Page 142:
Page 145 and 146:
Kim SO et al . Sorafenib-induced sp
Page 147 and 148:
Sahebkar A. Ginger as a natural sup
Page 149 and 150:
Page 151 and 152:
Instructions to authors Indexed and
Page 153 and 154:
Instructions to authors uniform leg
Page 155:
Instructions to authors Language ev
show all

Connective tissue growth factor reacts as an IL - World Journal of ...

Create successful ePaper yourself

Delete template?

Save as template?