Inhibition of heme oxygenase-1 increases responsiveness of pancreatic cancer cells to anticancer treatment.
Heme oxygenase-1 (HO-1) is believed to represent a key enzyme for the protection of cells against "stress." Its overexpression in different types of human cancers supports the notion that HO-1 provides a growth advantage and contributes to cellular resistance against chemotherapy and radiotherapy. Given the poor survival rates of patients with pancreatic cancer due to its aggressive growth behavior and its exceptional resistance to all known forms of anticancer treatment, we have investigated the expression of HO-1 in human pancreatic cancer cells growth behavior and prognosis. Expression of HO-1 was analyzed in human pancreatic cancer samples in comparison with normal pancreas by quantitative PCR, Western blot, and confocal microscopy. The influence of radiotherapy and chemotherapy on HO-1 expression in pancreatic cancer cell lines was evaluated. Furthermore, HO-1 expression was specifically suppressed by small interfering RNA transfection and subsequently the alterations of growth behavior and resistance to anticancer treatment were tested. Human pancreatic cancer showed a 6-fold and 3.5-fold HO-1 up-regulation in comparison to normal pancreas based on mRNA and protein level, respectively (P < 0.05). Cancer tissues revealed marked HO-1 immunoreactivity in tumor cells and in tumor associated immunocytes. Treatment of the pancreatic cancer cell lines with gemcitabine or radiation strongly induced HO-1 expression. Targeted knockdown of HO-1 expression led to pronounced growth inhibition of the pancreatic cancer cells and made tumor cells significantly more sensitive to radiotherapy and chemotherapy. Therefore, specific inhibition of HO-1 expression may be a new option in pancreatic cancer therapy and may be used as sensitizer to chemotherapy and radiotherapy.
Berberat
Pascal O
PO
Division of Pancreatic Surgery and Molecular Pancreatic Research, Department of General Surgery, Institute of Immunology, University of Heidelberg, Heidelberg, Germany.
Dambrauskas
Zilvinas
Z
Gulbinas
Antanas
A
Giese
Thomas
T
Giese
Nathalia
N
Künzli
Beat
B
Autschbach
Frank
F
Meuer
Stefen
S
Büchler
Markus W
MW
Friess
Helmut
H
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology*; D051547:Heme Oxygenase-1; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D018613:Microscopy, Confocal; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000473:pathology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D011836:Radiation Tolerance; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000970:Antineoplastic Agents; D008565:Membrane Proteins; D012333:RNA, Messenger; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1