title: Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells.
abstract: Metastasis-associated phosphatase of regenerating liver-3 (PRL-3) has pleiotropic effects in driving cancer progression, yet the signaling mechanisms of PRL-3 are still not fully understood. Here, we provide evidence for PRL-3-induced hyperactivation of EGFR and its downstream signaling cascades in multiple human cancer cell lines. Mechanistically, PRL-3-induced activation of EGFR was attributed primarily to transcriptional downregulation of protein tyrosine phosphatase 1B (PTP1B), an inhibitory phosphatase for EGFR. Functionally, PRL-3-induced hyperactivation of EGFR correlated with increased cell growth, promigratory characteristics, and tumorigenicity. Moreover, PRL-3 induced cellular addiction to EGFR signaling, as evidenced by the pronounced reversion of these oncogenic attributes upon EGFR-specific inhibition. Of clinical significance, we verified elevated PRL-3 expression as a predictive marker for favorable therapeutic response in a heterogeneous colorectal cancer (CRC) patient cohort treated with the clinically approved anti-EGFR antibody cetuximab. The identification of PRL-3-driven EGFR hyperactivation and consequential addiction to EGFR signaling opens new avenues for inhibiting PRL-3-driven cancer progression. We propose that elevated PRL-3 expression is an important clinical predictive biomarker for favorable anti-EGFR cancer therapy.
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore.
authors.forename: Abdul Qader Omer
authors.initials: AQ
authors.lastname: Al-Aidaroos
authors.forename: Hiu Fung
authors.initials: HF
authors.lastname: Yuen
authors.forename: Ke
authors.initials: K
authors.lastname: Guo
authors.forename: Shu Dong
authors.initials: SD
authors.lastname: Zhang
authors.forename: Tae-Hoon
authors.initials: TH
authors.lastname: Chung
authors.forename: Wee Joo
authors.initials: WJ
authors.lastname: Chng
authors.forename: Qi
authors.initials: Q
authors.lastname: Zeng
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002465:Cell Movement; D049109:Cell Proliferation; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D018572:Disease-Free Survival; D004794:Enzyme Repression; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D015398:Signal Transduction; D016896:Treatment Outcome; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D066246:ErbB Receptors; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C484730:PTP4A3 protein, human; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D000068818:Cetuximab