Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the beta4 integrin and the PI3k pathway.
Pancreatic ductal adenocarcinoma is a devastating disease, characterized by a rapid progression and poor treatment response. Using gene expression profiling of pancreatic cancer tissues, we previously identified periostin as a potential diagnostic and therapeutic target. In this study, we report the overexpression of periostin in a larger set of pancreatic cancer tissues and show that although the periostin transcript is exclusively expressed in tumour cells, the protein product is only detected in the extracellular matrix adjacent to cancer cells. Using an enzyme-linked immunosorbent assay (ELISA) assay, we show significantly increased levels of periostin in the sera of pancreatic cancer patients compared to non-cancer controls. We demonstrate that periostin promotes the invasiveness of tumour cells by increasing the motility of cells without inducing expression of proteases, and enhances the survival of tumour cells exposed to hypoxic conditions. At the molecular level, we provide evidence that the alpha(6)beta(4) integrin complex acts as the cell receptor of periostin in pancreatic cancer cells and that interaction promotes phosphorylation of focal adhesion kinase (FAK) and protein kinase B (AKT) though activation of the PI3 kinase pathway, but not the RAS/MEK/ERK pathway. These findings suggest an important role of periostin in pancreatic cancer and provide a rationale to study periostin for diagnostic and therapeutic applications.
Baril
P
P
Centre for Molecular Oncology, Institute of Cancer and the CR-UK Clinical Centre, Barts, UK.
Gangeswaran
R
R
Mahon
P C
PC
Caulee
K
K
Kocher
H M
HM
Harada
T
T
Zhu
M
M
Kalthoff
H
H
Crnogorac-Jurcevic
T
T
Lemoine
N R
NR
D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D039161:Integrin alpha6beta4 / Q000378:metabolism; D039663:Integrin beta4 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D014158:Transcription, Genetic
D015815:Cell Adhesion Molecules; D039161:Integrin alpha6beta4; D039663:Integrin beta4; C512835:POSTN protein, human; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt