Monoclonal antibodies target intracellular PRL phosphatases to inhibit cancer metastases in mice.
PRL-1 (phosphatase of regenerating liver-1), PRL-2 and PRL-3 are protein tyrosine phosphatases with a C-terminal prenylation motif that are localized to the inner leaflet of the plasma membrane and early endosomes. A variety of metastatic PRL-overexpressing cancers have been reported. Therefore, the three PRL-phosphatases represent an intriguing group of proteins being validated as biomarkers and therapeutic targets in cancer. Targeting intracellular PRLs to prevent cancer metastasis by exogenous reagents is a challenging task. In an attempt to destroy PRL-overexpressing cancer cells with their respective PRL-antibodies, we generated an animal model that allows rapid formation of aggressive metastatic tumors caused by inoculation of PRL-1- or PRL-3-expressing cells. Surprisingly, mice treated with PRL-1 or PRL-3 mAbs show inhibition of tumor formation by approximately 90% compared to untreated mice. Here we provide the first examples that PRL-1 and PRL-3 mAbs are able to target their respective phosphatases specifically and efficiently despite their intracellular localization to block cancer metastasis in experimental animals. Furthermore, we also demonstrate that PRL-1 mAb specifically blocks the formation of metastatic tumors formed by PRL-1- (but not PRL-3-) expressing cells; while PRL-3 mAb specifically blocks tumor formation of PRL-3- (but not PRL-1-) expressing cells. More importantly, we show that metastatic tumor formation by A2780 human ovarian cancer cells that express endogenous PRL-3 is dramatically blocked by PRL-3 antibodies. In contrast, the PRL-3 antibody treatment has no effect on tumor formation of CT26 mouse colon cancer cells which do not naturally express PRL-3 protein. Our data provide hope for the treatment of PRL-expressing cancers and will prompt a reevaluation of a wide spectrum of intracellular oncoproteins as possible targets with mAbs for anticancer therapy.
Guo
Ke
K
Institute of Molecular and Cell Biology, Proteos, Singapore, Singapore.
Tang
Jing Ping
JP
Tan
Cheng Peow Bobby
CP
Wang
Haihe
H
Zeng
Qi
Q
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000494:pharmacology; D016466:CHO Cells; D018797:Cell Cycle Proteins / Q000737:chemistry*; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry*; D051379:Mice; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; C490198:PTP4A1 protein, human; C487561:PTP4A2 protein, human; D017027:Protein Tyrosine Phosphatases