Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells
Abdul Qader Omer Al-aidaroos, … , Wee Joo Chng, Qi Zeng
Abdul Qader Omer Al-aidaroos, … , Wee Joo Chng, Qi Zeng
Published July 8, 2013
Citation Information: J Clin Invest. 2013;123(8):3459-3471. https://doi.org/10.1172/JCI66824.
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Research Article Oncology

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

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

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Figure 4

EGFR-specific inhibitors block PRL-3–induced dissolution of stress fibers and F-actin enrichment at membrane protrusions.

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EGFR-specific inhibitors block PRL-3–induced dissolution of stress fiber...
(A–D) MDA-MB-468-vec (A and B) or MDA-MB-468-PRL-3 (C and D) cells were seeded on glass coverslips and incubated with 0.1% DMSO (A and C) or 2 μM erlotinib (B and D) 16 hours prior to fixing. Fixed cells were stained with phalloidin to visualize F-actin stress fibers. Scale bars: 20 μm. (E–H) MDA-MB-468-vec (E and F) or MDA-MB-468-PRL-3 (G and H) cells were seeded on glass coverslips and incubated with PBS (E and G) or 100 nM cetuximab (F and H) 16 hours prior to fixing. Fixed cells were stained with phalloidin to visualize F-actin enrichment. Arrows indicate sites of F-actin–rich membrane projections. Green, EGFP signal; red, F-actin. Scale bars: 20 μm.