Mechanism of PRL2 phosphatase-mediated PTEN degradation and tumorigenesis

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Significance

The PRL phosphatases are highly oncogenic when overexpressed. However, the mechanism by which they promote tumorigenesis is unknown. Here, we reveal PTEN as a putative PRL2 substrate and define a mechanism for PTEN degradation through PRL2-mediated PTEN dephosphorylation. These insights immediately place the PRL2 phosphatase into the PI3K/AKT pathway, one of the critical signaling networks altered in cancer. We further demonstrate in a preclinical model that removal of Prl2 in Pten ^+/− mice increases the level of PTEN and inhibits PTEN heterozygosity-induced tumorigenesis. Given the observed inverse correlation between PRL2 expression and PTEN level, targeting PRL2 serves as a potential PTEN restoration strategy to treat cancers caused by PTEN deficiency.

Abstract

Tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) levels are frequently found reduced in human cancers, but how PTEN is down-regulated is not fully understood. In addition, although a compelling connection exists between PRL (phosphatase of regenerating liver) 2 and cancer, how this phosphatase induces oncogenesis has been an enigma. Here, we discovered that PRL2 ablation inhibits PTEN heterozygosity-induced tumorigenesis. PRL2 deficiency elevates PTEN and attenuates AKT signaling, leading to decreased proliferation and increased apoptosis in tumors. We also found that high PRL2 expression is correlated with low PTEN level with reduced overall patient survival. Mechanistically, we identified PTEN as a putative PRL2 substrate and demonstrated that PRL2 down-regulates PTEN by dephosphorylating PTEN at Y336, thereby augmenting NEDD4-mediated PTEN ubiquitination and proteasomal degradation. Given the strong cancer susceptibility to subtle reductions in PTEN, the ability of PRL2 to down-regulate PTEN provides a biochemical basis for its oncogenic propensity. The results also suggest that pharmacological targeting of PRL2 could provide a novel therapeutic strategy to restore PTEN, thereby obliterating PTEN deficiency-induced malignancies.

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Is Open Access

Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: From laboratory to patients.

Filip Janku (2017)

The phosphoinositide 3-kinase (PI3K) pathway is an intracellular signaling pathway that has regulatory roles in cell survival, proliferation, and differentiation, and a critical role in tumorigenesis. In cancer, multiple studies have investigated the therapeutic targeting of the PI3K pathway, and multiple inhibitors targeting PI3K and its isoforms, protein kinase B/AKT, mammalian target of rapamycin (mTOR), and other pathway proteins have been developed. For the treatment of solid tumors, only allosteric mTOR inhibitors, such as everolimus and temsirolimus, are currently approved for clinical use. This review describes the PI3K inhibitors that have progressed from the laboratory to late-stage clinical trials, and discusses the challenges that have prevented other compounds from doing the same. Challenges to the therapeutic effectiveness of some PI3K inhibitors include the absence of reliable and effective biomarkers, their limited efficacy as single agents, insufficient development of rational therapeutic combinations, the use of schedules with a variety of off-target effects, and suboptimal therapeutic exposures. Therefore, with regard to PI3K inhibitors currently in late-stage clinical trials, the identification of appropriate biomarkers of efficacy and the development of optimal combination regimens and dosing schedules are likely to be important for graduation into clinical practice.

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Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc. Natl. Acad. Sci. U.S.A

Journal ID (hwp): pnas

Journal ID (pmc): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Print): 25 August 2020

Publication date (Electronic): 11 August 2020

Volume: 117

Issue: 34

Pages: 20538-20548

Affiliations

[1] ^aDepartment of Medicinal Chemistry and Molecular Pharmacology, Purdue University , West Lafayette, IN 47907;

[2] ^bDepartment of Comparative Pathobiology, Purdue University , West Lafayette, IN 47907;

[3] ^cCenter for Cancer Research, Purdue University , West Lafayette, IN 47907;

[4] ^dDepartment of Chemistry, Purdue University , West Lafayette, IN 47907;

[5] ^eInstitute for Drug Discovery, Purdue University , West Lafayette, IN 47907

Author notes

²To whom correspondence may be addressed. Email: zhang-zy@ 123456purdue.edu .

Edited by Vuk Stambolic, Princess Margaret Cancer Centre, Toronto, Canada, and accepted by Editorial Board Member Tak W. Mak July 9, 2020 (received for review February 19, 2020)

Author contributions: Q.L., Y.B., and Z.-Y.Z. designed research; Q.L., Y.B., G.Y., O.A., F.N.M., and C.C. performed research; Q.L., Y.B., L.T.L., and Z.-Y.Z. analyzed data; and Q.L., Y.B., L.T.L., and Z.-Y.Z. wrote the paper.

¹Q.L. and Y.B. contributed equally to this work.