Therapeutic significance of elevated tissue transglutaminase expression in pancreatic cancer.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
siRNA-mediated down-regulation of TG2 represents a promising therapeutic approach for improved treatment of PDAC.
Verma
Amit
A
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Guha
Sushovan
S
Diagaradjane
Parmeswaran
P
Kunnumakkara
Ajaikumar B
AB
Sanguino
Angela M
AM
Lopez-Berestein
Gabriel
G
Sood
Anil K
AK
Aggarwal
Bharat B
BB
Krishnan
Sunil
S
Gelovani
Juri G
JG
Mehta
Kapil
K
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019204:GTP-Binding Proteins; D020868:Gene Silencing; D006801:Humans; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000628:therapy*; D010713:Phosphatidylcholines / Q000008:administration & dosage; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000235:genetics
D010713:Phosphatidylcholines; D034741:RNA, Small Interfering; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; C017251:1,2-oleoylphosphatidylcholine