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      Synthetic lethal approaches to target cancers with loss of PTEN function

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          Abstract

          Phosphatase and tensin homolog ( PTEN) is a tumor suppressor gene and has a role in inhibiting the oncogenic AKT signaling pathway by dephosphorylating phosphatidylinositol 3,4,5-triphosphate (PIP 3) into phosphatidylinositol 4,5-bisphosphate (PIP 2). The function of PTEN is regulated by different mechanisms and inactive PTEN results in aggressive tumor phenotype and tumorigenesis. Identifying targeted therapies for inactive tumor suppressor genes such as PTEN has been challenging as it is difficult to restore the tumor suppressor functions. Therefore, focusing on the downstream signaling pathways to discover a targeted therapy for inactive tumor suppressor genes has highlighted the importance of synthetic lethality studies. This review focused on the potential synthetic lethality genes discovered in PTEN-inactive cancer types. These discovered genes could be potential targeted therapies for PTEN-inactive cancer types and may improve the treatment response rates for aggressive types of cancer.

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          Understanding the Warburg effect: the metabolic requirements of cell proliferation.

          Craig B Thompson, Matthew Vander Heiden, Lewis Cantley (2009)
          In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed "the Warburg effect." Aerobic glycolysis is an inefficient way to generate adenosine 5'-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.
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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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              Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.

              Hannah L. Farmer, Nuala McCabe, Christopher J. Lord … (2005)
              BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.
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                Author and article information

                Contributors
                Ayse Ertay
                Yihua Wang
                Journal
                Journal ID (nlm-ta): Genes Dis
                Journal ID (iso-abbrev): Genes Dis
                Title: Genes & Diseases
                Publisher: Chongqing Medical University
                ISSN (Print): 2352-4820
                ISSN (Electronic): 2352-3042
                Publication date PMC-release: 01 February 2023
                Publication date Collection: November 2023
                Publication date (Electronic): 01 February 2023
                Volume: 10
                Issue: 6
                Pages: 2511-2527
                Affiliations
                [a ]Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
                [b ]Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK
                Author notes
                [∗ ]Corresponding author. A.Ertay@ 123456soton.ac.uk
                [∗∗ ]Corresponding author. Biological Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton SO17 1BJ, UK. yihua.wang@ 123456soton.ac.uk
                Article
                Publisher Item ID: S2352-3042(23)00012-0
                DOI: 10.1016/j.gendis.2022.12.015
                PMC ID: 7614861
                PubMed ID: 37533462
                SO-VID: 9228a051-9c60-4319-b226-c27dfaa984e5
                Copyright © © 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 16 October 2022
                Date revision received : 26 December 2022
                Date accepted : 27 December 2022
                Categories
                Subject: Review Article

                Keywords: cancer,pten,synthetic lethality,tumour suppressor gene,wdhd1
                Data availability:
                Keywords: cancer, pten, synthetic lethality, tumour suppressor gene, wdhd1

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