TY - JOUR
T1 - Therapeutic significance of elevated tissue transglutaminase expression in pancreatic cancer
AU - Verma, Amit
AU - Guha, Sushovan
AU - Diagaradjane, Parmeswaran
AU - Kunnumakkara, Ajaikumar B.
AU - Sanguino, Angela M.
AU - Lopez-Berestein, Gabriel
AU - Sood, Anil K.
AU - Aggarwal, Bharat B.
AU - Krishnan, Sunil
AU - Gelovani, Juri G.
AU - Mehta, Kapil
PY - 2008/4/15
Y1 - 2008/4/15
N2 - Purpose: Tissue transglutaminase (TG2) is a multifunctional protein that is implicated in development of drug resistance and metastasis. Therefore, we examined therapeutic targeting of TG2 for inhibiting growth and metastasis of in vivo growing pancreatic ductal adenocarcinoma (PDAC) in nude mice. Experimental Design: We implanted Panc-28 pancreatic cancer cells to induce orthotopic PDAC tumors in nude mice and determined the efficacy of liposomal TG2 small interfering RNA (siRNA) either alone or in combination with gemcitabine. Results: We show that down-regulation of endogenous TG2 by siRNA could effectively block the growth of PDAC. Moreover, down-regulation of TG2 significantly enhanced the therapeutic efficacy of gemcitabine against PDAC and inhibited metastatic spread of the disease. The antitumor activity was related to inhibition of proliferation, angiogenesis, and Akt phosphorylation. Conclusion: siRNA-mediated down-regulation of TG2 represents a promising therapeutic approach for improved treatment of PDAC.
AB - Purpose: Tissue transglutaminase (TG2) is a multifunctional protein that is implicated in development of drug resistance and metastasis. Therefore, we examined therapeutic targeting of TG2 for inhibiting growth and metastasis of in vivo growing pancreatic ductal adenocarcinoma (PDAC) in nude mice. Experimental Design: We implanted Panc-28 pancreatic cancer cells to induce orthotopic PDAC tumors in nude mice and determined the efficacy of liposomal TG2 small interfering RNA (siRNA) either alone or in combination with gemcitabine. Results: We show that down-regulation of endogenous TG2 by siRNA could effectively block the growth of PDAC. Moreover, down-regulation of TG2 significantly enhanced the therapeutic efficacy of gemcitabine against PDAC and inhibited metastatic spread of the disease. The antitumor activity was related to inhibition of proliferation, angiogenesis, and Akt phosphorylation. Conclusion: siRNA-mediated down-regulation of TG2 represents a promising therapeutic approach for improved treatment of PDAC.
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U2 - 10.1158/1078-0432.CCR-07-4529
DO - 10.1158/1078-0432.CCR-07-4529
M3 - Article
C2 - 18413840
AN - SCOPUS:42249109822
SN - 1078-0432
VL - 14
SP - 2476
EP - 2483
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -