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Title: Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells
Authors: Al-Aidaroos, A.Q.O.
Yuen, H.F.
Guo, K.
Zhang, S.D.
Chung, T.-H. 
Chng, W.J.
Zeng, Q. 
Issue Date: 1-Aug-2013
Source: Al-Aidaroos, A.Q.O., Yuen, H.F., Guo, K., Zhang, S.D., Chung, T.-H., Chng, W.J., Zeng, Q. (2013-08-01). Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells. Journal of Clinical Investigation 123 (8) : 3459-3471. ScholarBank@NUS Repository.
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.
Source Title: Journal of Clinical Investigation
ISSN: 00219738
DOI: 10.1172/JCI66824
Appears in Collections:Staff Publications

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