Therapy of human pancreatic carcinoma based on suppression of HMGA1 protein synthesis in preclinical models.
Pancreatic carcinoma is one of the most aggressive tumors, and, being refractory to conventional therapies, is an excellent target for new therapeutic approaches. Based on our previous finding of high HMGA1 expression in pancreatic cancer cells compared to normal pancreatic tissue, we evaluated whether suppression of HMGA1 protein expression could be a treatment option for patients affected by pancreatic cancer. Here we report that HMGA1 proteins are overexpressed in pancreatic carcinoma cell lines, and their downregulation through an adenovirus carrying the HMGA1 gene in an antisense orientation (Ad Yas-GFP) results in the death of three human pancreatic carcinoma cell lines (PANC1, Hs766T and PSN1). Pretreatment of PANC1 and PSN1 cells with Ad Yas-GFP suppressed and reduced, respectively, their ability to form xenograft tumors in nude mice. To further verify the role of HMGA1 in pancreatic tumorigenesis, we used a HMGA1 antisense phosphorothioate oligodeoxynucleotide (ODN); its addition induced a decrease in HMGA1 protein levels and a significant reduction of the proliferation rate of PANC1-, Hs766T- and PSN1-treated cells. Therefore, suppression of HMGA1 protein synthesis by an HMGA1 antisense approach seems to be a feasible treatment strategy in pancreatic carcinomas.
Dipartimento di Biologia e Patologia Cellulare e Molecolare, c/o Centro di Endocrinologia ed Oncologia Sperimentale del CNR, Università di Napoli Federico II, Naples, Italy.
Francesco
F
Trapasso
Manuela
M
Sarti
Rossano
R
Cesari
Sai
S
Yendamuri
Kristoffel R
KR
Dumon
Rami I
RI
Aqeilan
Francesca
F
Pentimalli
Luisa
L
Infante
Hansjuerg
H
Alder
Nobutsugu
N
Abe
Takashi
T
Watanabe
Giuseppe
G
Viglietto
Carlo M
CM
Croce
Alfredo
A
Fusco
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D025741:HMGA1a Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D023421:Models, Animal; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000628:therapy*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D016376:Oligonucleotides, Antisense; D025741:HMGA1a Protein; D049452:Green Fluorescent Proteins