A selective phosphatase of regenerating liver phosphatase inhibitor suppresses tumor cell anchorage-independent growth by a novel mechanism involving p130Cas cleavage.
The phosphatase of regenerating liver (PRL) family, a unique class of oncogenic phosphatases, consists of three members: PRL-1, PRL-2, and PRL-3. Aberrant overexpression of PRL-3 has been found in multiple solid tumor types. Ectopic expression of PRLs in cells induces transformation, increases mobility and invasiveness, and forms experimental metastases in mice. We have now shown that small interfering RNA-mediated depletion of PRL expression in cancer cells results in the down-regulation of p130Cas phosphorylation and expression and prevents tumor cell anchorage-independent growth in soft agar. We have also identified a small molecule, 7-amino-2-phenyl-5H-thieno[3,2-c]pyridin-4-one (thienopyridone), which potently and selectively inhibits all three PRLs but not other phosphatases in vitro. The thienopyridone showed significant inhibition of tumor cell anchorage-independent growth in soft agar, induction of the p130Cas cleavage, and anoikis, a type of apoptosis that can be induced by anticancer agents via disruption of cell-matrix interaction. Unlike etoposide, thienopyridone-induced p130Cas cleavage and apoptosis were not associated with increased levels of p53 and phospho-p53 (Ser(15)), a hallmark of genotoxic drug-induced p53 pathway activation. This is the first report of a potent selective PRL inhibitor that suppresses tumor cell three-dimensional growth by a novel mechanism involving p130Cas cleavage. This study reveals a new insight into the role of PRL-3 in priming tumor progression and shows that PRL may represent an attractive target for therapeutic intervention in cancer.
Daouti
Sherif
S
Preclinical Research, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110, USA.
Li
Wen-hui
WH
Qian
Hong
H
Huang
Kuo-Sen
KS
Holmgren
Janna
J
Levin
Wayne
W
Reik
Linda
L
McGady
Debra Lucas
DL
Gillespie
Paul
P
Perrotta
Agostino
A
Bian
Hongjin
H
Reidhaar-Olson
John F
JF
Bliss
Sarah A
SA
Olivier
Andree R
AR
Sergi
Joseph A
JA
Fry
David
D
Danho
Waleed
W
Ritland
Steve
S
Fotouhi
Nader
N
Heimbrook
David
D
Niu
Huifeng
H
D000595:Amino Acid Sequence; D000818:Animals; D023102:Anoikis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D050719:Crk-Associated Substrate Protein / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D011725:Pyridines; D034741:RNA, Small Interfering; C446540:thienopyridine; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases