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Microtubule Dynamics and Cancer

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

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 40692

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Dr. Nina-Naomi Kreis

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Guest Editor

Department of Gynecology and Obstetrics, University Hospital, J. W. Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany
Interests: p21/CDKN1A; cell cycle regulation; mitosis; cell migration/invasion; stem cells; microtubule dynamics; placenta; preeclampsia; the primary cilium; small molecule inhibitors

Dr. Andreas Ritter

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Guest Editor

Department of Gynecology and Obstetrics, University Hospital, J. W. Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany
Interests: stem cells; differentiation; epithelial–mesenchymal transition; primary cilia; obesity; microtubule dynamics; cell cycle regulation; mitosis; small molecule inhibitors and cancer-associated fibroblast

Special Issue Information

Dear Colleagues,

Microtubules are highly dynamic key components of the cytoskeleton composed of alpha- and beta-tubulin heterodimers. Microtubule dynamics are tightly regulated by various microtubule-associated proteins, kinases, and phosphatases. Proper regulation of microtubule dynamics is not only important for mitosis and faithful chromosome segregation but also for cell signaling, trafficking, cell migration, and ciliogenesis. Defects in spindle assembly or the separation of the duplicated chromosomes into daughter cells may lead to cell death or genomic instability, causes for diseases such as developmental disorders and cancer. Given their indispensable role in cell division and in diverse cellular processes, microtubules have served as pharmacologically validated and attractive targets for cancer therapy for decades.

Understanding how the microtubule cytoskeleton is formed and regulated in somatic and malignant cells will help us to improve treatment strategies for cancer patients. For this purpose, the identification of proteins modulating the microtubule network could lead to a better understanding of chromosome instability and tumor progression and provide additional prognostic information for the selection of adequate anti-cancer therapy for patients to significantly optimize clinical outcomes.

We invite contributions in the form of original research articles, short communications, or reviews related to microtubule dynamics and cancer.

Dr. Nina-Naomi Kreis
Dr. Andreas Ritter
Guest Editors

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Keywords

microtubule dynamics
cytoskeleton
mitotic spindle
segregation
microtubule-associated proteins
microtubule-interfering drugs
small molecule inhibitors
migration
primary cilium
epithelial-mesenchymal transition

Published Papers (12 papers)

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Editorial

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4 pages, 193 KiB

Open AccessEditorial

Microtubule Dynamics and Cancer

by Andreas Ritter and Nina-Naomi Kreis

Cancers 2022, 14(18), 4368; https://doi.org/10.3390/cancers14184368 - 8 Sep 2022

Cited by 3 | Viewed by 1423

Abstract

Microtubules (MTs) are highly dynamic key components of the cytoskeleton composed of alpha- and beta-tubulin heterodimers [...] Full article

(This article belongs to the Special Issue Microtubule Dynamics and Cancer)

Research

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22 pages, 3027 KiB

Open AccessArticle

Tubulin Carboxypeptidase Activity Promotes Focal Gelatin Degradation in Breast Tumor Cells and Induces Apoptosis in Breast Epithelial Cells That Is Overcome by Oncogenic Signaling

by Trevor J. Mathias, Julia A. Ju, Rachel M. Lee, Keyata N. Thompson, Makenzy L. Mull, David A. Annis, Katarina T. Chang, Eleanor C. Ory, Megan B. Stemberger, Takashi Hotta, Ryoma Ohi, Michele I. Vitolo, Marie-Jo Moutin and Stuart S. Martin

Cancers 2022, 14(7), 1707; https://doi.org/10.3390/cancers14071707 - 28 Mar 2022

Cited by 3 | Viewed by 2281

Abstract

Post-translational modifications (PTMs) of the microtubule network impart differential functions across normal cell types and their cancerous counterparts. The removal of the C-terminal tyrosine of α-tubulin (deTyr-Tub) as performed by the tubulin carboxypeptidase (TCP) is of particular interest in breast epithelial and breast cancer cells. The recent discovery of the genetic identity of the TCP to be a vasohibin (VASH1/2) coupled with a small vasohibin-binding protein (SVBP) allows for the functional effect of this tubulin PTM to be directly tested for the first time. Our studies revealed the immortalized breast epithelial cell line MCF10A undergoes apoptosis following transfection with TCP constructs, but the addition of oncogenic KRas or Bcl-2/Bcl-xL overexpression prevents subsequent apoptotic induction in the MCF10A background. Functionally, an increase in deTyr-Tub via TCP transfection in MDA-MB-231 and Hs578t breast cancer cells leads to enhanced focal gelatin degradation. Given the elevated deTyr-Tub at invasive tumor fronts and the correlation with poor breast cancer survival, these new discoveries help clarify how the TCP synergizes with oncogene activation, increases focal gelatin degradation, and may correspond to increased tumor cell invasion. These connections could inform more specific microtubule-directed therapies to target deTyr-tubulin. Full article

(This article belongs to the Special Issue Microtubule Dynamics and Cancer)

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16 pages, 3060 KiB

Open AccessArticle

Microtentacle Formation in Ovarian Carcinoma

by Jocelyn C. Reader, Cong Fan, Eleanor Claire-Higgins Ory, Julia Ju, Rachel Lee, Michele I. Vitolo, Paige Smith, Sulan Wu, Mc Millan Nicol Ching, Emmanuel B. Asiedu, Christopher M. Jewell, Gautam G. Rao, Amy Fulton, Tonya J. Webb, Peixin Yang, Alessandro D. Santin, Huang-Chiao Huang, Stuart S. Martin and Dana M. Roque

Cancers 2022, 14(3), 800; https://doi.org/10.3390/cancers14030800 - 4 Feb 2022

Cited by 4 | Viewed by 2949

Abstract

Background: The development of chemoresistance to paclitaxel and carboplatin represents a major therapeutic challenge in ovarian cancer, a disease frequently characterized by malignant ascites and extrapelvic metastasis. Microtentacles (McTNs) are tubulin-based projections observed in detached breast cancer cells. In this study, we investigated whether ovarian cancers exhibit McTNs and characterized McTN biology. Methods: We used an established lipid-tethering mechanism to suspend and image individual cancer cells. We queried a panel of immortalized serous (OSC) and clear cell (OCCC) cell lines as well as freshly procured ascites and human ovarian surface epithelium (HOSE). We assessed by Western blot β-tubulin isotype, α-tubulin post-translational modifications and actin regulatory proteins in attached/detached states. We studied clustering in suspended conditions. Effects of treatment with microtubule depolymerizing and stabilizing drugs were described. Results: Among cell lines, up to 30% of cells expressed McTNs. Four McTN morphologies (absent, symmetric-short, symmetric-long, tufted) were observed in immortalized cultures as well as ascites. McTN number/length varied with histology according to metastatic potential. Most OCCC overexpressed class III ß-tubulin. OCCC/OSC cell lines exhibited a trend towards more microtubule-stabilizing post-translational modifications of α-tubulin relative to HOSE. Microtubule depolymerizing drugs decreased the number/length of McTNs, confirming that McTNs are composed of tubulin. Cells that failed to form McTNs demonstrated differential expression of α-tubulin- and actin-regulating proteins relative to cells that form McTNs. Cluster formation is more susceptible to microtubule targeting agents in cells that form McTNs, suggesting a role for McTNs in aggregation. Conclusions: McTNs likely participate in key aspects of ovarian cancer metastasis. McTNs represent a new therapeutic target for this disease that could refine therapies, including intraperitoneal drug delivery. Full article

(This article belongs to the Special Issue Microtubule Dynamics and Cancer)

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17 pages, 6318 KiB

Open AccessArticle

TH588 and Low-Dose Nocodazole Impair Chromosome Congression by Suppressing Microtubule Turnover within the Mitotic Spindle

by Girish Rajendraprasad, Susana Eibes, Claudia Guasch Boldú and Marin Barisic

Cancers 2021, 13(23), 5995; https://doi.org/10.3390/cancers13235995 - 29 Nov 2021

Cited by 8 | Viewed by 2910

Abstract

Microtubule-targeting agents (MTAs) have been used for decades to treat different hematologic and solid cancers. The mode of action of these drugs mainly relies on their ability to bind tubulin subunits and/or microtubules and interfere with microtubule dynamics. In addition to its MTH1-inhibiting activity, TH588 has been recently identified as an MTA, whose anticancer properties were shown to largely depend on its microtubule-targeting ability. Although TH588 inhibited tubulin polymerization in vitro and reduced microtubule plus-end mobility in interphase cells, its effect on microtubule dynamics within the mitotic spindle of dividing cells remained unknown. Here, we performed an in-depth analysis of the impact of TH588 on spindle-associated microtubules and compared it to the effect of low-dose nocodazole. We show that both treatments reduce microtubule turnover within the mitotic spindle. This microtubule-stabilizing effect leads to premature formation of kinetochore-microtubule end-on attachments on uncongressed chromosomes, which consequently cannot be transported to the cell equator, thereby delaying cell division and leading to cell death or division with uncongressed chromosomes. Full article

(This article belongs to the Special Issue Microtubule Dynamics and Cancer)

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24 pages, 67443 KiB

Open AccessArticle

Mitotic Centromere-Associated Kinesin (MCAK/KIF2C) Regulates Cell Migration and Invasion by Modulating Microtubule Dynamics and Focal Adhesion Turnover

by Ha Hyung Moon, Nina-Naomi Kreis, Alexandra Friemel, Susanne Roth, Dorothea Schulte, Christine Solbach, Frank Louwen, Juping Yuan and Andreas Ritter

Cancers 2021, 13(22), 5673; https://doi.org/10.3390/cancers13225673 - 12 Nov 2021

Cited by 18 | Viewed by 2645

Abstract

The microtubule (MT) cytoskeleton is crucial for cell motility and migration by regulating multiple cellular activities such as transport and endocytosis of key components of focal adhesions (FA). The kinesin-13 family is important in the regulation of MT dynamics and the best characterized member of this family is the mitotic centromere-associated kinesin (MCAK/KIF2C). Interestingly, its overexpression has been reported to be related to increased metastasis in various tumor entities. Moreover, MCAK is involved in the migration and invasion behavior of various cell types. However, the precise molecular mechanisms were not completely clarified. To address these issues, we generated CRISPR/dCas9 HeLa and retinal pigment epithelium (RPE) cell lines overexpressing or downregulating MCAK. Both up- or downregulation of MCAK led to reduced cell motility and poor migration in malignant as well as benign cells. Specifically, it’s up- or downregulation impaired FA protein composition and phosphorylation status, interfered with a proper spindle and chromosome segregation, disturbed the assembly and disassembly rate of FA, delayed cell adhesion, and compromised the plus-tip dynamics of MTs. In conclusion, our data suggest MCAK act as an important regulator for cell motility and migration by affecting the actin-MT cytoskeleton dynamics and the FA turnover, providing molecular mechanisms by which deregulated MCAK could promote malignant progression and metastasis of tumor cells. Full article

(This article belongs to the Special Issue Microtubule Dynamics and Cancer)

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14 pages, 2623 KiB

Open AccessArticle

Characterization of Microtubule Destabilizing Drugs: A Quantitative Cell-Based Assay That Bridges the Gap between Tubulin Based- and Cytotoxicity Assays

by Marie-Catherine Laisne, Sophie Michallet and Laurence Lafanechère

Cancers 2021, 13(20), 5226; https://doi.org/10.3390/cancers13205226 - 18 Oct 2021

Cited by 7 | Viewed by 2851

Abstract

(1) Background: Microtubule depolymerizing agents (MDAs) are commonly used for cancer treatment. However, the therapeutic use of such microtubule inhibitors is limited by their toxicity and the emergence of resistance. Thus, there is still a sustained effort to develop new MDAs. During the characterization of such agents, mainly through in vitro analyses using purified tubulin and cytotoxicity assays, quantitative comparisons are mandatory. The relationship between the effect of the drugs on purified tubulin and on cell viability are not always direct. (2) Methods: We have recently developed a cell-based assay that quantifies the cellular microtubule content. In this study, we have conducted a systematic comparative analysis of the effect of four well-characterized MDAs on the kinetics of in vitro tubulin assembly, on the cellular microtubule content (using our recently developed assay) and on cell viability. (3) Conclusions: These assays gave complementary results. Additionally, we found that the drugs’ effect on in vitro tubulin polymerization is not completely predictive of their relative cytotoxicity. Their effect on the cellular microtubule content, however, is closely related to their effect on cell viability. In conclusion, the assay we have recently developed can bridge the gap between in vitro tubulin assays and cell viability assays. Full article

(This article belongs to the Special Issue Microtubule Dynamics and Cancer)

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Review

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21 pages, 2539 KiB

Open AccessReview

CK1 Is a Druggable Regulator of Microtubule Dynamics and Microtubule-Associated Processes

by Aileen Roth, Adrian Gihring, Joachim Bischof, Leiling Pan, Franz Oswald and Uwe Knippschild

Cancers 2022, 14(5), 1345; https://doi.org/10.3390/cancers14051345 - 5 Mar 2022

Cited by 8 | Viewed by 3784

Abstract

Protein kinases of the Casein Kinase 1 family play a vital role in the regulation of numerous cellular processes. Apart from functions associated with regulation of proliferation, differentiation, or apoptosis, localization of several Casein Kinase 1 isoforms to the centrosome and microtubule asters also implicates regulatory functions in microtubule dynamic processes. Being localized to the spindle apparatus during mitosis Casein Kinase 1 directly modulates microtubule dynamics by phosphorylation of tubulin isoforms. Additionally, site-specific phosphorylation of microtubule-associated proteins can be related to the maintenance of genomic stability but also microtubule stabilization/destabilization, e.g., by hyper-phosphorylation of microtubule-associated protein 1A and RITA1. Consequently, approaches interfering with Casein Kinase 1-mediated microtubule-specific functions might be exploited as therapeutic strategies for the treatment of cancer. Currently pursued strategies include the development of Casein Kinase 1 isoform-specific small molecule inhibitors and therapeutically useful peptides specifically inhibiting kinase-substrate interactions. Full article

(This article belongs to the Special Issue Microtubule Dynamics and Cancer)

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21 pages, 17511 KiB

Open AccessReview

The Tubulin Code and Tubulin-Modifying Enzymes in Autophagy and Cancer

by Daniela Trisciuoglio and Francesca Degrassi

Cancers 2022, 14(1), 6; https://doi.org/10.3390/cancers14010006 - 21 Dec 2021

Cited by 14 | Viewed by 4464

Abstract

Microtubules are key components of the cytoskeleton of eukaryotic cells. Microtubule dynamic instability together with the “tubulin code” generated by the choice of different α- and β- tubulin isoforms and tubulin post-translational modifications have essential roles in the control of a variety of cellular processes, such as cell shape, cell motility, and intracellular trafficking, that are deregulated in cancer. In this review, we will discuss available evidence that highlights the crucial role of the tubulin code in determining different cancer phenotypes, including metastatic cell migration, drug resistance, and tumor vascularization, and the influence of modulating tubulin-modifying enzymes on cancer cell survival and aggressiveness. We will also discuss the role of post-translationally modified microtubules in autophagy—the lysosomal-mediated cellular degradation pathway—that exerts a dual role in many cancer types, either promoting or suppressing cancer growth. We will give particular emphasis to the role of tubulin post-translational modifications and their regulating enzymes in controlling the different stages of the autophagic process in cancer cells, and consider how the experimental modulation of tubulin-modifying enzymes influences the autophagic process in cancer cells and impacts on cancer cell survival and thereby represents a new and fruitful avenue in cancer therapy. Full article

(This article belongs to the Special Issue Microtubule Dynamics and Cancer)

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20 pages, 841 KiB

Open AccessReview

Microtubule-Interfering Drugs: Current and Future Roles in Epithelial Ovarian Cancer Treatment

by Joan Tymon-Rosario, Naomi N. Adjei, Dana M. Roque and Alessandro D. Santin

Cancers 2021, 13(24), 6239; https://doi.org/10.3390/cancers13246239 - 12 Dec 2021

Cited by 16 | Viewed by 3166

Abstract

Taxanes and epothilones are chemotherapeutic agents that ultimately lead to cell death through inhibition of normal microtubular function. This review summarizes the literature demonstrating their current use and potential promise as therapeutic agents in the treatment of epithelial ovarian cancer (EOC), as well as putative mechanisms of resistance. Historically, taxanes have become the standard of care in the front-line and recurrent treatment of epithelial ovarian cancer. In the past few years, epothilones (i.e., ixabepilone) have become of interest as they may retain activity in taxane-treated patients since they harbor several features that may overcome mechanisms of taxane resistance. Clinical data now support the use of ixabepilone in the treatment of platinum-resistant or refractory ovarian cancer. Clinical data strongly support the use of microtubule-interfering drugs alone or in combination in the treatment of epithelial ovarian cancer. Ongoing clinical trials will shed further light into the potential of making these drugs part of current standard practice. Full article

(This article belongs to the Special Issue Microtubule Dynamics and Cancer)

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21 pages, 3479 KiB

Open AccessReview

Microtubule-Based Mitochondrial Dynamics as a Valuable Therapeutic Target in Cancer

by Rosa Vona, Anna Maria Mileo and Paola Matarrese

Cancers 2021, 13(22), 5812; https://doi.org/10.3390/cancers13225812 - 19 Nov 2021

Cited by 23 | Viewed by 3840

Abstract

Mitochondria constitute an ever-reorganizing dynamic network that plays a key role in several fundamental cellular functions, including the regulation of metabolism, energy production, calcium homeostasis, production of reactive oxygen species, and programmed cell death. Each of these activities can be found to be impaired in cancer cells. It has been reported that mitochondrial dynamics are actively involved in both tumorigenesis and metabolic plasticity, allowing cancer cells to adapt to unfavorable environmental conditions and, thus, contributing to tumor progression. The mitochondrial dynamics include fusion, fragmentation, intracellular trafficking responsible for redistributing the organelle within the cell, biogenesis, and mitophagy. Although the mitochondrial dynamics are driven by the cytoskeleton—particularly by the microtubules and the microtubule-associated motor proteins dynein and kinesin—the molecular mechanisms regulating these complex processes are not yet fully understood. More recently, an exchange of mitochondria between stromal and cancer cells has also been described. The advantage of mitochondrial transfer in tumor cells results in benefits to cell survival, proliferation, and spreading. Therefore, understanding the molecular mechanisms that regulate mitochondrial trafficking can potentially be important for identifying new molecular targets in cancer therapy to interfere specifically with tumor dissemination processes. Full article

(This article belongs to the Special Issue Microtubule Dynamics and Cancer)

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22 pages, 1515 KiB

Open AccessReview

Microtubule Targeting Agents in Disease: Classic Drugs, Novel Roles

by Linda Wordeman and Juan Jesus Vicente

Cancers 2021, 13(22), 5650; https://doi.org/10.3390/cancers13225650 - 12 Nov 2021

Cited by 54 | Viewed by 5931

Abstract

Microtubule-targeting agents (MTAs) represent one of the most successful first-line therapies prescribed for cancer treatment. They interfere with microtubule (MT) dynamics by either stabilizing or destabilizing MTs, and in culture, they are believed to kill cells via apoptosis after eliciting mitotic arrest, among other mechanisms. This classical view of MTA therapies persisted for many years. However, the limited success of drugs specifically targeting mitotic proteins, and the slow growing rate of most human tumors forces a reevaluation of the mechanism of action of MTAs. Studies from the last decade suggest that the killing efficiency of MTAs arises from a combination of interphase and mitotic effects. Moreover, MTs have also been implicated in other therapeutically relevant activities, such as decreasing angiogenesis, blocking cell migration, reducing metastasis, and activating innate immunity to promote proinflammatory responses. Two key problems associated with MTA therapy are acquired drug resistance and systemic toxicity. Accordingly, novel and effective MTAs are being designed with an eye toward reducing toxicity without compromising efficacy or promoting resistance. Here, we will review the mechanism of action of MTAs, the signaling pathways they affect, their impact on cancer and other illnesses, and the promising new therapeutic applications of these classic drugs. Full article

(This article belongs to the Special Issue Microtubule Dynamics and Cancer)

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16 pages, 1296 KiB

Open AccessReview

Dysregulation of Microtubule Nucleating Proteins in Cancer Cells

by Pavel Dráber and Eduarda Dráberová

Cancers 2021, 13(22), 5638; https://doi.org/10.3390/cancers13225638 - 11 Nov 2021

Cited by 10 | Viewed by 2735

Abstract

In cells, microtubules typically nucleate from microtubule organizing centers, such as centrosomes. γ-Tubulin, which forms multiprotein complexes, is essential for nucleation. The γ-tubulin ring complex (γ-TuRC) is an efficient microtubule nucleator that requires additional centrosomal proteins for its activation and targeting. Evidence suggests that there is a dysfunction of centrosomal microtubule nucleation in cancer cells. Despite decades of molecular analysis of γ-TuRC and its interacting factors, the mechanisms of microtubule nucleation in normal and cancer cells remains obscure. Here, we review recent work on the high-resolution structure of γ-TuRC, which brings new insight into the mechanism of microtubule nucleation. We discuss the effects of γ-TuRC protein dysregulation on cancer cell behavior and new compounds targeting γ-tubulin. Drugs inhibiting γ-TuRC functions could represent an alternative to microtubule targeting agents in cancer chemotherapy. Full article

(This article belongs to the Special Issue Microtubule Dynamics and Cancer)

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