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Cancers
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Cell Cycle and Cell Cycle Checkpoint Deregulations: From Oncogenic Drivers...
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Cell Cycle and Cell Cycle Checkpoint Deregulations: From Oncogenic Drivers to Therapeutic Targets

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

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 28943

Special Issue Editor

Dr. Roberta Visconti

E-Mail Website
Guest Editor
Institute of Experimental Endocrinology and Oncology “G. Salvatore”, Italian National Council of Research, Via S. Pansini 5, 80131 Napoli, Italy
Interests: cell cycle; mitosis; phosphatases; Fcp1; antimicrotubule cancer drugs; Wee1 inhibitors; biomarkers

Special Issue Information

Dear Colleagues,

Cell cycle deregulation is a hallmark of cancer. Cell cycle core proteins are frequently mutated in human tumors. Moreover, cancer cells often have defective cell cycle checkpoints; thus, progression along the cycle is permitted also to cells bearing DNA damage or chromosome segregation errors.

For this Special Issue we invite original research papers and reviews discussing update information about the normal cell cycle machinery and the mechanisms causing its oncogenic switch. Papers and reviews about the development of novel drugs directed against cell cycle targets are also welcomed. Finally, we encourage the submission of manuscripts focusing on how defects in cell cycle checkpoints, while apparently advantageous for cancer cell uncontrolled proliferation, can be exploited to directly promote cell death or to increase vulnerability to major currently used therapeutics.

Looking forward to your contributions.

Dr. Roberta Visconti
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 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

  • cell cycle regulators
  • cell cycle checkpoints
  • cancer cell cycle
  • targeted therapy
  • combination therapies

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Published Papers (6 papers)

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Research

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22 pages, 3847 KiB  
Article
Differential Effects of Combined ATR/WEE1 Inhibition in Cancer Cells
by Gro Elise Rødland, Sissel Hauge, Grete Hasvold, Lilli T. E. Bay, Tine T. H. Raabe, Mrinal Joel and Randi G. Syljuåsen
Cancers 2021, 13(15), 3790; https://doi.org/10.3390/cancers13153790 - 28 Jul 2021
Cited by 16 | Viewed by 3927
Abstract
Inhibitors of WEE1 and ATR kinases are considered promising for cancer treatment, either as monotherapy or in combination with chemo- or radiotherapy. Here, we addressed whether simultaneous inhibition of WEE1 and ATR might be advantageous. Effects of the WEE1 inhibitor MK1775 and ATR [...] Read more.
Inhibitors of WEE1 and ATR kinases are considered promising for cancer treatment, either as monotherapy or in combination with chemo- or radiotherapy. Here, we addressed whether simultaneous inhibition of WEE1 and ATR might be advantageous. Effects of the WEE1 inhibitor MK1775 and ATR inhibitor VE822 were investigated in U2OS osteosarcoma cells and in four lung cancer cell lines, H460, A549, H1975, and SW900, with different sensitivities to the WEE1 inhibitor. Despite the differences in cytotoxic effects, the WEE1 inhibitor reduced the inhibitory phosphorylation of CDK, leading to increased CDK activity accompanied by ATR activation in all cell lines. However, combining ATR inhibition with WEE1 inhibition could not fully compensate for cell resistance to the WEE1 inhibitor and reduced cell viability to a variable extent. The decreased cell viability upon the combined treatment correlated with a synergistic induction of DNA damage in S-phase in U2OS cells but not in the lung cancer cells. Moreover, less synergy was found between ATR and WEE1 inhibitors upon co-treatment with radiation, suggesting that single inhibitors may be preferable together with radiotherapy. Altogether, our results support that combining WEE1 and ATR inhibitors may be beneficial for cancer treatment in some cases, but also highlight that the effects vary between cancer cell lines. Full article
(This article belongs to the Special Issue Cell Cycle and Cell Cycle Checkpoint Deregulations: From Oncogenic Drivers to Therapeutic Targets)
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20 pages, 5587 KiB  
Article
Silencing CDCA8 Suppresses Hepatocellular Carcinoma Growth and Stemness via Restoration of ATF3 Tumor Suppressor and Inactivation of AKT/β–Catenin Signaling
by Taewon Jeon, Min Ji Ko, Yu-Ri Seo, Soo-Jung Jung, Daekwan Seo, So-Young Park, Keon Uk Park, Kwang Seok Kim, Mikyung Kim, Ji Hae Seo, In-Chul Park, Min-Ji Kim, Jae-Hoon Bae, Dae-Kyu Song, Chi Heum Cho, Jae-Ho Lee and Yun-Han Lee
Cancers 2021, 13(5), 1055; https://doi.org/10.3390/cancers13051055 - 2 Mar 2021
Cited by 38 | Viewed by 4101
Abstract
Big data analysis has revealed the upregulation of cell division cycle associated 8 (CDCA8) in human hepatocellular carcinoma (HCC) and its poorer survival outcome. However, the functions of CDCA8 during HCC development remain unknown. Here, we demonstrate in vitro that CDCA8 silencing inhibits [...] Read more.
Big data analysis has revealed the upregulation of cell division cycle associated 8 (CDCA8) in human hepatocellular carcinoma (HCC) and its poorer survival outcome. However, the functions of CDCA8 during HCC development remain unknown. Here, we demonstrate in vitro that CDCA8 silencing inhibits HCC cell growth and long-term colony formation and migration through the accumulation of the G2/M phase cell population. Conversely, CDCA8 overexpression increases the ability to undergo long-term colony formation and migration. RNA sequencing and bioinformatic analysis revealed that CDCA8 knockdown led to the same directional regulation in 50 genes (25 down- and 25 upregulated). It was affirmed based on protein levels that CDCA8 silencing downregulates the levels of cyclin B1 and p-cdc2 and explains how it could induce G2/M arrest. The same condition increased the protein levels of tumor-suppressive ATF3 and GADD34 and inactivated AKT/β–catenin signaling, which plays an important role in cell growth and stemness, reflecting a reduction in sphere-forming capacity. Importantly, it was demonstrated that the extent of CDCA8 expression is much greater in CD133+ cancer stem cells than in CD133− cancer cells, and that CDCA8 knockdown decreases levels of CD133, p-Akt and β-catenin and increases levels of ATF3 and GADD34 in the CD133+ cancer stem cell (CSC) population. These molecular changes led to the inhibition of cell growth and sphere formation in the CD133+ cell population. Targeting CDCA8 also effectively suppressed tumor growth in a murine xenograft model, showing consistent molecular alterations in tumors injected with CDCA8siRNA. Taken together, these findings indicate that silencing CDCA8 suppresses HCC growth and stemness via restoring the ATF3 tumor suppressor and inactivating oncogenic AKT/β–catenin signaling, and that targeting CDCA8 may be the next molecular strategy for both primary HCC treatment and the prevention of metastasis or recurrence. Full article
(This article belongs to the Special Issue Cell Cycle and Cell Cycle Checkpoint Deregulations: From Oncogenic Drivers to Therapeutic Targets)
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14 pages, 4097 KiB  
Article
Increased Expression of NPM1 Suppresses p27Kip1 Function in Cancer Cells
by Tatsuya Kometani, Takuya Arai and Taku Chibazakura
Cancers 2020, 12(10), 2886; https://doi.org/10.3390/cancers12102886 - 8 Oct 2020
Cited by 3 | Viewed by 2405
Abstract
p27Kip1, a major cyclin-dependent kinase inhibitor, is frequently expressed at low levels in cancers, which correlates with their malignancy. However, in this study, we found a qualitative suppression of p27 overexpressed in some cancer cells. By proteomic screening for factors interacting [...] Read more.
p27Kip1, a major cyclin-dependent kinase inhibitor, is frequently expressed at low levels in cancers, which correlates with their malignancy. However, in this study, we found a qualitative suppression of p27 overexpressed in some cancer cells. By proteomic screening for factors interacting with p27, we identified nucleophosmin isoform 1 (NPM1) as a novel p27-interacting factor and observed that NPM1 protein was expressed at high levels in some cancer cells. NPM1 overexpression in normal cells suppressed p27 function, and conversely, NPM1 knockdown in cancer cells restored the function in vitro. Furthermore, the tumors derived from cancer cells carrying the combination of p27 overexpression and NPM1 knockdown constructs showed significant suppression of growth as compared with those carrying other combinations in mouse xenograft models. These results strongly suggest that increased expression of NPM1 qualitatively suppresses p27 function in cancer cells. Full article
(This article belongs to the Special Issue Cell Cycle and Cell Cycle Checkpoint Deregulations: From Oncogenic Drivers to Therapeutic Targets)
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18 pages, 14604 KiB  
Article
NSCLC Mutated Isoforms of CCDC6 Affect the Intracellular Distribution of the Wild Type Protein Promoting Cisplatinum Resistance and PARP Inhibitors Sensitivity in Lung Cancer Cells
by Aniello Cerrato, Francesco Morra, Imma Di Domenico and Angela Celetti
Cancers 2020, 12(1), 44; https://doi.org/10.3390/cancers12010044 - 21 Dec 2019
Cited by 7 | Viewed by 3690
Abstract
CCDC6 is implicated in cell cycle checkpoints and DNA damage repair by homologous recombination (HR). In NSCLC, CCDC6 is barely expressed in about 30% of patients and CCDC6 gene rearrangements with RET and ROS kinases are detected in about 1% of patients. Recently, [...] Read more.
CCDC6 is implicated in cell cycle checkpoints and DNA damage repair by homologous recombination (HR). In NSCLC, CCDC6 is barely expressed in about 30% of patients and CCDC6 gene rearrangements with RET and ROS kinases are detected in about 1% of patients. Recently, CCDC6 point-mutations naming E227K, S351Y, N394Y, and T462A have been identified in primary NSCLC. In this work, we analyze the effects exerted by the CCDC6 mutated isoforms on lung cancer cells. By pull-down experiments and immunofluorescence, we evaluated the biochemical and morphological effects of CCDC6 lung-mutants on the CCDC6 wild type protein. By using two HR-reporter assays, we analyzed the effect of CCDC6 lung-mutants in perturbing CCDC6 physiology in the HR process. Finally, by cell-titer assay, we evaluated the response to the treatment with different drugs in lung cancer cells expressing CCDC6 mutants. This work shows that the CCDC6 mutated and truncated isoforms, identified so far in NSCLC, affected the intracellular distribution of the wild type protein and impaired the CCDC6 function in the HR process, ultimately inducing cisplatinum resistance and PARP-inhibitors sensitivity in lung cancer cells. The identification of selected molecular alterations involving CCDC6 gene product might define predictive biomarkers for personalized treatment in NSCLC. Full article
(This article belongs to the Special Issue Cell Cycle and Cell Cycle Checkpoint Deregulations: From Oncogenic Drivers to Therapeutic Targets)
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Review

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19 pages, 1562 KiB  
Review
Under-Replicated DNA: The Byproduct of Large Genomes?
by Agustina P. Bertolin, Jean-Sébastien Hoffmann and Vanesa Gottifredi
Cancers 2020, 12(10), 2764; https://doi.org/10.3390/cancers12102764 - 25 Sep 2020
Cited by 22 | Viewed by 3437
Abstract
In this review, we provide an overview of how proliferating eukaryotic cells overcome one of the main threats to genome stability: incomplete genomic DNA replication during S phase. We discuss why it is currently accepted that double fork stalling (DFS) events are unavoidable [...] Read more.
In this review, we provide an overview of how proliferating eukaryotic cells overcome one of the main threats to genome stability: incomplete genomic DNA replication during S phase. We discuss why it is currently accepted that double fork stalling (DFS) events are unavoidable events in higher eukaryotes with large genomes and which responses have evolved to cope with its main consequence: the presence of under-replicated DNA (UR-DNA) outside S phase. Particular emphasis is placed on the processes that constrain the detrimental effects of UR-DNA. We discuss how mitotic DNA synthesis (MiDAS), mitotic end joining events and 53BP1 nuclear bodies (53BP1-NBs) deal with such specific S phase DNA replication remnants during the subsequent phases of the cell cycle. Full article
(This article belongs to the Special Issue Cell Cycle and Cell Cycle Checkpoint Deregulations: From Oncogenic Drivers to Therapeutic Targets)
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17 pages, 7600 KiB  
Review
FUCCI Real-Time Cell-Cycle Imaging as a Guide for Designing Improved Cancer Therapy: A Review of Innovative Strategies to Target Quiescent Chemo-Resistant Cancer Cells
by Shuya Yano, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara and Robert M. Hoffman
Cancers 2020, 12(9), 2655; https://doi.org/10.3390/cancers12092655 - 17 Sep 2020
Cited by 19 | Viewed by 10316
Abstract
Progress in chemotherapy of solid cancer has been tragically slow due, in large part, to the chemoresistance of quiescent cancer cells in tumors. The fluorescence ubiquitination cell-cycle indicator (FUCCI) was developed in 2008 by Miyawaki et al., which color-codes the phases of the [...] Read more.
Progress in chemotherapy of solid cancer has been tragically slow due, in large part, to the chemoresistance of quiescent cancer cells in tumors. The fluorescence ubiquitination cell-cycle indicator (FUCCI) was developed in 2008 by Miyawaki et al., which color-codes the phases of the cell cycle in real-time. FUCCI utilizes genes linked to different color fluorescent reporters that are only expressed in specific phases of the cell cycle and can, thereby, image the phases of the cell cycle in real-time. Intravital real-time FUCCI imaging within tumors has demonstrated that an established tumor comprises a majority of quiescent cancer cells and a minor population of cycling cancer cells located at the tumor surface or in proximity to tumor blood vessels. In contrast to most cycling cancer cells, quiescent cancer cells are resistant to cytotoxic chemotherapy, most of which target cells in S/G2/M phases. The quiescent cancer cells can re-enter the cell cycle after surviving treatment, which suggests the reason why most cytotoxic chemotherapy is often ineffective for solid cancers. Thus, quiescent cancer cells are a major impediment to effective cancer therapy. FUCCI imaging can be used to effectively target quiescent cancer cells within tumors. For example, we review how FUCCI imaging can help to identify cell-cycle-specific therapeutics that comprise decoy of quiescent cancer cells from G1 phase to cycling phases, trapping the cancer cells in S/G2 phase where cancer cells are mostly sensitive to cytotoxic chemotherapy and eradicating the cancer cells with cytotoxic chemotherapy most active against S/G2 phase cells. FUCCI can readily image cell-cycle dynamics at the single cell level in real-time in vitro and in vivo. Therefore, visualizing cell cycle dynamics within tumors with FUCCI can provide a guide for many strategies to improve cell-cycle targeting therapy for solid cancers. Full article
(This article belongs to the Special Issue Cell Cycle and Cell Cycle Checkpoint Deregulations: From Oncogenic Drivers to Therapeutic Targets)
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