Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells

Abdul Qader Omer Al-Aidaroos, Hiu Fung Yuen, Ke Guo, Shu-Dong Zhang, Tae-Hoon Chung, Wee Joo Chng, Qi Zeng

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)
196 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)3459-3471
JournalThe Journal of clinical investigation
Volume123
Issue number8
Early online date08 Jul 2013
DOIs
Publication statusPublished - 01 Aug 2013

ASJC Scopus subject areas

  • Medicine(all)

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