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 5

PRL-3–overexpressing cells are hypersensitive to EGFR-specific inhibitors.

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PRL-3–overexpressing cells are hypersensitive to EGFR-specific inhibitor...
(A) Representative immunoblots of serum-starved A431-vec and A431-PRL-3 cells treated with DMSO or AG-1478 (AG) 75 minutes before lysis. Lane pairs were run on the same gel but were noncontiguous. Normalized densitometric ratios of phosphoproteins/total proteins are indicated below selected blots. (B) Representative immunoblots of serum-starved A431-vec and A431-PRL-3 treated with PBS or cetuximab (CTX) 24 hours before lysis. Lane pairs were run on the same gel but were noncontiguous. (C) Representative immunoblots of serum-starved MDA-MB-468-vec and MDA-MB-468-PRL-3 cells treated with DMSO, AG-1478 (75 minutes), or erlotinib (3 hours) before lysis. (D) A431-vec or A431-PRL-3 cell growth after 48-hour exposure to DMSO, cisplatin, AG-1478, erlotinib, or cetuximab in 0.5% FBS medium (mean ± standard deviation; n = 3; unpaired Student’s t test, *P < 0.05, **P < 0.001). Black bars, A431-vec; white bars, A431-PRL-3. Arrows indicate a hypersensitive response. (E) A431-vec and A431-PRL-3 cell colony score after 11 days of treatment with PBS or 20 nM cetuximab in 10% FBS medium (mean ± standard deviation; n = 2; unpaired Student’s t test, *P < 0.05). Arrow indicates a hypersensitive response. Representative images of colony formation are shown in the right panel. (F) Growth curves of A431-vec or A431-PRL-3 xenograft tumors treated i.p. with 1 mg cetuximab or 200 μl PBS twice weekly for 2 weeks (mean ± standard deviation; *P < 0.05). (G) Comparison of day 14 tumor volumes from F (Student’s t test, *P < 0.05, **P < 0.001).