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Protein Synthesis in Cancer Cells: Mechanisms and Novel Targeted Therapies

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 15954

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Special Issue Editor

Dr. Mikael S. Lindström

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Guest Editor

Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Box 1031, 171 21 Stockholm, Sweden
Interests: glioblastoma; glioma; ribosome biogenesis; nucleolus; p53; DNA damage response in cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In human cancers, oncogenes often induce profound and rapid cell growth associated with an increase in overall protein synthesis. The synthesis of proteins can be controlled at many levels including through the production of new ribosomes. The selective synthesis of proteins that affect cancer cell growth or confer resistance to treatment may be altered at the stage of translation initiation. Many existing and emerging anticancer therapeutic agents inhibit cancer cell growth by interfering with nucleotide metabolism, transcription by RNA polymerases, or translation. Recent studies have revealed links between oncogenic factors, nucleotide metabolism, and ribosome biogenesis in various cancers. In fact, cancer cells may become dependent on a high level of ribosome biogenesis, specific alterations in the ribosomal machinery, or deregulated translation. Such functional alterations that ultimately affect cancer cell protein synthesis and growth represent opportunities to develop novel anticancer therapies.
This Special Issue of Cancers, “Protein Synthesis in Cancer Cells: Mechanisms and Novel Targeted Therapies”, is devoted to compiling new research articles and timely reviews on the topic of protein synthesis in cancer cells. Specifically, we welcome submissions on ribosome biogenesis in cancer, ribosomal stress and p53, how the translational machinery is corrupted in the growing cancer cell (for example, by the use of cancer cell-specific ribosomes and modifications of rRNA), or rewiring of protein synthesis through translation factors. In particular, we welcome studies on how these cellular processes can be targeted by present or emerging novel targeted therapeutics, for example, by using mTOR, Myc, or RNA polymerase I inhibitors. Manuscripts dealing with the development of biomarkers related to ribosome biogenesis, the nucleolus, or mRNA translation in cancer are also of great interest.

Dr. Mikael S. Lindström
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

ribosome biogenesis
cancer cell growth
protein synthesis
targeted therapy
nucleolus
mRNA translation
RNA polymerase I
transcription inhibitor
ribosomal protein
nucleolus
nucleolar stress
nucleotide metabolism

Published Papers (3 papers)

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Research

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17 pages, 2391 KiB

Open AccessArticle

Nucleolar Stress Functions Upstream to Stimulate Expression of Autophagy Regulators

by David P. Dannheisig, Anna Schimansky, Cornelia Donow and Astrid S. Pfister

Cancers 2021, 13(24), 6220; https://doi.org/10.3390/cancers13246220 - 10 Dec 2021

Cited by 7 | Viewed by 2565

Abstract

Ribosome biogenesis is essential for protein synthesis, cell growth and survival. The process takes places in nucleoli and is orchestrated by various proteins, among them RNA polymerases I–III as well as ribosome biogenesis factors. Perturbation of ribosome biogenesis activates the nucleolar stress response, which classically triggers cell cycle arrest and apoptosis. Nucleolar stress is utilized in modern anti-cancer therapies, however, also contributes to the development of various pathologies, including cancer. Growing evidence suggests that nucleolar stress stimulates compensatory cascades, for instance bulk autophagy. However, underlying mechanisms are poorly understood. Here we demonstrate that induction of nucleolar stress activates expression of key autophagic regulators such as ATG7 and ATG16L1, essential for generation of autophagosomes. We show that knockdown of the ribosomopathy factor SBDS, or of key ribosome biogenesis factors (PPAN, NPM, PES1) is associated with enhanced levels of ATG7 in cancer cells. The same holds true when interfering with RNA polymerase I function by either pharmacological inhibition (CX-5461) or depletion of the transcription factor UBF-1. Moreover, we demonstrate that RNA pol I inhibition by CX-5461 stimulates autophagic flux. Together, our data establish that nucleolar stress affects transcriptional regulation of autophagy. Given the contribution of both axes in propagation or cure of cancer, our data uncover a connection that might be targeted in future. Full article

(This article belongs to the Special Issue Protein Synthesis in Cancer Cells: Mechanisms and Novel Targeted Therapies)

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Review

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29 pages, 1944 KiB

Open AccessEditor’s ChoiceReview

Targeting Ribosome Biogenesis in Cancer: Lessons Learned and Way Forward

by Asimina Zisi, Jiri Bartek and Mikael S. Lindström

Cancers 2022, 14(9), 2126; https://doi.org/10.3390/cancers14092126 - 24 Apr 2022

Cited by 24 | Viewed by 5693

Abstract

Rapid growth and unrestrained proliferation is a hallmark of many cancers. To accomplish this, cancer cells re-wire and increase their biosynthetic and metabolic activities, including ribosome biogenesis (RiBi), a complex, highly energy-consuming process. Several chemotherapeutic agents used in the clinic impair this process by interfering with the transcription of ribosomal RNA (rRNA) in the nucleolus through the blockade of RNA polymerase I or by limiting the nucleotide building blocks of RNA, thereby ultimately preventing the synthesis of new ribosomes. Perturbations in RiBi activate nucleolar stress response pathways, including those controlled by p53. While compounds such as actinomycin D and oxaliplatin effectively disrupt RiBi, there is an ongoing effort to improve the specificity further and find new potent RiBi-targeting compounds with improved pharmacological characteristics. A few recently identified inhibitors have also become popular as research tools, facilitating our advances in understanding RiBi. Here we provide a comprehensive overview of the various compounds targeting RiBi, their mechanism of action, and potential use in cancer therapy. We discuss screening strategies, drug repurposing, and common problems with compound specificity and mechanisms of action. Finally, emerging paths to discovery and avenues for the development of potential biomarkers predictive of therapeutic outcomes across cancer subtypes are also presented. Full article

(This article belongs to the Special Issue Protein Synthesis in Cancer Cells: Mechanisms and Novel Targeted Therapies)

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23 pages, 1558 KiB

Open AccessReview

The Cap-Binding Complex CBC and the Eukaryotic Translation Factor eIF4E: Co-Conspirators in Cap-Dependent RNA Maturation and Translation

by Jean-Clement Mars, Mehdi Ghram, Biljana Culjkovic-Kraljacic and Katherine L. B. Borden

Cancers 2021, 13(24), 6185; https://doi.org/10.3390/cancers13246185 - 08 Dec 2021

Cited by 10 | Viewed by 3878

Abstract

The translation of RNA into protein is a dynamic process which is heavily regulated during normal cell physiology and can be dysregulated in human malignancies. Its dysregulation can impact selected groups of RNAs, modifying protein levels independently of transcription. Integral to their suitability for translation, RNAs undergo a series of maturation steps including the addition of the m⁷G cap on the 5′ end of RNAs, splicing, as well as cleavage and polyadenylation (CPA). Importantly, each of these steps can be coopted to modify the transcript signal. Factors that bind the m⁷G cap escort these RNAs through different steps of maturation and thus govern the physical nature of the final transcript product presented to the translation machinery. Here, we describe these steps and how the major m⁷G cap-binding factors in mammalian cells, the cap binding complex (CBC) and the eukaryotic translation initiation factor eIF4E, are positioned to chaperone transcripts through RNA maturation, nuclear export, and translation in a transcript-specific manner. To conceptualize a framework for the flow and integration of this genetic information, we discuss RNA maturation models and how these integrate with translation. Finally, we discuss how these processes can be coopted by cancer cells and means to target these in malignancy. Full article

(This article belongs to the Special Issue Protein Synthesis in Cancer Cells: Mechanisms and Novel Targeted Therapies)

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