PTEN/PTENP1: ‘Regulating the regulator of RTK-dependent PI3K/Akt signalling’, new targets for cancer therapy

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Abstract

Regulation of the PI-3 kinase (PI3K)/Akt signalling pathway is essential for maintaining the integrity of fundamental cellular processes, cell growth, survival, death and metabolism, and dysregulation of this pathway is implicated in the development and progression of cancers. Receptor tyrosine kinases (RTKs) are major upstream regulators of PI3K/Akt signalling. The phosphatase and tensin homologue (PTEN), a well characterised tumour suppressor, is a prime antagonist of PI3K and therefore a negative regulator of this pathway. Loss or inactivation of PTEN, which occurs in many tumour types, leads to overactivation of RTK/PI3K/Akt signalling driving tumourigenesis. Cellular PTEN levels are tightly regulated by a number of transcriptional, post-transcriptional and post-translational regulatory mechanisms. Of particular interest, transcription of the PTEN pseudogene, PTENP1, produces sense and antisense transcripts that exhibit post-transcriptional and transcriptional modulation of PTEN expression respectively. These additional levels of regulatory complexity governing PTEN expression add to the overall intricacies of the regulation of RTK/PI-3 K/Akt signalling. This review will discuss the regulation of oncogenic PI3K signalling by PTEN (the regulator) with a focus on the modulatory effects of the sense and antisense transcripts of PTENP1 on PTEN expression, and will further explore the potential for new therapeutic opportunities in cancer treatment.

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Most cited references 135

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A coding-independent function of gene and pseudogene mRNAs regulates tumour biology

Laura Poliseno, Leonardo Salmena, JiangWen Zhang … (2010)

The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis. However, given that microRNAs bind to RNAs, we hypothesized that RNAs possess a biological role in cancer cells that relies upon their ability to compete for microRNA binding and is independent of their protein-coding function. As a paradigm for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene (PTENP1) and the critical consequences of this interaction. We find that PTENP1 is biologically active as determined by its ability to regulate cellular levels of PTEN, and that it can exert a growth-suppressive role. We also show that PTENP1 locus is selectively lost in human cancer. We extend our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS. Further, we demonstrate that the transcripts of protein coding genes such as PTEN are also biologically active. Together, these findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs.

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Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs.

Yvonne Tay, Lev Kats, Leonardo Salmena … (2011)

Here, we demonstrate that protein-coding RNA transcripts can crosstalk by competing for common microRNAs, with microRNA response elements as the foundation of this interaction. We have termed such RNA transcripts as competing endogenous RNAs (ceRNAs). We tested this hypothesis in the context of PTEN, a key tumor suppressor whose abundance determines critical outcomes in tumorigenesis. By a combined computational and experimental approach, we identified and validated endogenous protein-coding transcripts that regulate PTEN, antagonize PI3K/AKT signaling, and possess growth- and tumor-suppressive properties. Notably, we also show that these genes display concordant expression patterns with PTEN and copy number loss in cancers. Our study presents a road map for the prediction and validation of ceRNA activity and networks and thus imparts a trans-regulatory function to protein-coding mRNAs. Copyright © 2011 Elsevier Inc. All rights reserved.

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An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer.

Katherine Stemke-Hale, Ana Maria Gonzalez-Angulo, Ana Lluch … (2008)

Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy-based sequencing and reverse-phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT, and PTEN mutations and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor-positive (34.5%) and HER2-positive (22.7%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor-positive cancers. Unlike AKT1 mutations that were absent from cell lines, PIK3CA (39%) and PTEN (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not AKT1 mutations during adaptation to culture. PIK3CA mutations did not have a significant effect on outcome after adjuvant tamoxifen therapy in 157 hormone receptor-positive breast cancer patients. PIK3CA mutations, in comparison with PTEN loss and AKT1 mutations, were associated with significantly less and inconsistent activation of AKT and of downstream PI3K/AKT signaling in tumors and cell lines. PTEN loss and PIK3CA mutation were frequently concordant, suggesting different contributions to pathophysiology. PTEN loss rendered cells significantly more sensitive to growth inhibition by the PI3K inhibitor LY294002 than did PIK3CA mutations. Thus, PI3K pathway aberrations likely play a distinct role in the pathogenesis of different breast cancer subtypes. The specific aberration present may have implications for the selection of PI3K-targeted therapies in hormone receptor-positive breast cancer.

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Author and article information

Contributors

Nahal Haddadi: Nahal.Haddadi@student.uts.edu.au

Yiguang Lin: Yiguang.Lin@uts.edu.au

Glena Travis: Glena.Travis@student.uts.edu.au

Ann M. Simpson: Ann.Simpson@uts.edu.au

Eileen M. McGowan: +61 405814048 , Eileen.McGowan@uts.edu.au

Najah T. Nassif: +61 2 9514 4023 , Najah.Nassif@uts.edu.au

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol. Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 19 February 2018

Publication date PMC-release: 19 February 2018

Publication date Collection: 2018

Volume: 17

Electronic Location Identifier: 37

Affiliations

[1 ]ISNI 0000 0004 1936 7611, GRID grid.117476.2, School of Life Sciences, , Faculty of Science, University of Technology Sydney, ; 15 Broadway, Ultimo, Sydney, NSW 2007 Australia

[2 ]ISNI 0000 0004 1758 4014, GRID grid.477976.c, Central Laboratory, , The First Affiliated Hospital of Guangdong Pharmaceutical University, ; Guangzhou, 510080 China

Article

Publisher ID: 803

DOI: 10.1186/s12943-018-0803-3

PMC ID: 5817727

PubMed ID: 29455665

SO-VID: ecc9ce9d-8de3-4cdc-9bb8-71256b992389

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 15 October 2017

Date accepted : 1 February 2018

Funding

Funded by: Centre for Health Technologies, University of Technology Sydney

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: phosphatase and tensin homologue (pten),ptenp1,pseudogene,tyrosine kinase,pi-3 kinase (pi3k),cancer,microrna (mirna)

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: phosphatase and tensin homologue (pten), ptenp1, pseudogene, tyrosine kinase, pi-3 kinase (pi3k), cancer, microrna (mirna)

PTEN/PTENP1: ‘Regulating the regulator of RTK-dependent PI3K/Akt signalling’, new targets for cancer therapy

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Karger: Oncology

Most cited references 135

A coding-independent function of gene and pseudogene mRNAs regulates tumour biology

Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs.

An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer.

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