Too MAD or not MAD enough: The duplicitous role of the spindle assembly checkpoint protein MAD2 in cancer

Bates, Mark; Furlong, Fiona; Gallagher, Michael; Spillane, Cathy; McCann, Amanda; O’Toole, Sharon; O’Leary, John

doi:10.1016/j.canlet.2019.10.005

Cited by 23 publications

(13 citation statements)

References 94 publications

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“…This is critical for stem cell self-renewal and differentiation 9 , 10 . The role of several checkpoint proteins has been studied in cancer, like MAD2 and BUBR1, and the levels of these proteins have been associated with tumorigenesis or clinical prognosis 11 - 13 .…”

Section: Introductionmentioning

confidence: 99%

Targeting MAD2 modulates stemness and tumorigenesis in human Gastric Cancer cell lines

et al. 2020

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Rationale: Gastric cancer (GC) is a solid tumor that contains subpopulations of cancer stem cells (CSCs), which are considered drivers of tumor initiation and metastasis; responsible for therapeutic resistance; and promoters of tumor relapse. The balance between symmetric and asymmetric division is crucial for stem cell maintenance. The objective of this study is to evaluate the role of MAD2, a key protein for proper mitotic checkpoint activity, in the tumorigenesis of GC. Methods: Gastric cancer stem cells (GCSCs) were obtained from MKN45, SNU638 and ST2957 cell lines. Pluripotency and stemness markers were evaluated by RT-qPCR and autofluorescence and membrane markers by flow cytometry. Relevant signal transduction pathways were studied by WB. We analysed cell cycle progression, migration and invasion after modulation of MAD2 activity or protein expression levels in these in vitro models. In vivo assays were performed in a nude mouse subcutaneous xenograft model. Results: We found that NANOG , CXCR4 and autofluorescence are common and consistent markers for the GCSCs analysed, with other markers showing more variability. The three main signalling pathways (Wnt/β-catenin; Hedgehog and Notch) were activated in GCSCs. Downregulation of MAD2 in MKN45 CSCs decreased the expression of markers CXCR4, CD133, CD90, LGR5 and VIM , without affecting cell cycle profile or therapy resistance. Moreover, migration, invasion and tumor growth were clearly reduced, and accordingly, we found that metalloprotease expression decreased. These results were accompanied by a reduction in the levels of transcription factors related with epithelial-to-mesenchymal transition. Conclusions: We can conclude that MAD2 is important for GCSCs stemness and its downregulation in MKN45 CSCs plays a central role in GC tumorigenesis, likely through CXCR4- SNAI2 -MMP1. Thus, its potential use in the clinical setting should be studied as its functions appear to extend beyond mitosis.

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Section: Introductionmentioning

confidence: 99%

Targeting MAD2 modulates stemness and tumorigenesis in human Gastric Cancer cell lines

et al. 2020

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“…Therefore, these patients may benefit from miR-433 antagomir therapy. A variety of other anti-senescence therapies are available which may help boost paclitaxel efficacy when MAD2 or miR-433 are used as triage markers [26,87]. The results also demonstrate that these senescent cell populations appear to be selectively resistant to paclitaxel but are sensitive to carboplatin, therefore patients could potentially be selected out for single arm therapy with carboplatin.…”

Section: Fig 7 Altered Genes and Biological Processes Following Knockdown Of Mad2 String Network Analysis And Cross Comparison Of The Madmentioning

confidence: 89%

“…Among those affected were genes involved in OR activity and the response to a number of different chemical and extracellular stimuli, IGFBP activity and ossification, cell motility, lipase & phospholipase activity and arachidonic acid metabolism, DNA packaging and ion transporter activity. Senescent cells likely act as a protective barrier against paclitaxel and perhaps other chemotherapeutic agents, shielding non-senescent populations of cancer cells such as CSCs from drug-induced cell death while simultaneously promoting their growth through the milieu of cytokines they release as part of the SASP [26,27]. Previous reports have demonstrated that senescent cells are capable of promoting the growth of tumours and induce the progression of pre-malignant lesions into malignant tumours in in-vivo xenografts [73,74].…”

Section: Fig 7 Altered Genes and Biological Processes Following Knockdown Of Mad2 String Network Analysis And Cross Comparison Of The Madmentioning

confidence: 99%

“…Suppression of MAD2 leads to mitotic catastrophe as cells divide without proper chromosomal segregation. This leads to anaphase bridge formation and generation of a DNA damage response which mimics normal telomere shortening resulting in the induction of cellular senescence [5,26]. Cellular senescence allows tumour cells to resist paclitaxel which only targets actively dividing cells while also promoting tumour growth through the release of a milieu of over 40 different cytokines/chemokines and other factors as part of what is known as the senescence associated secretory phenotype (SASP) [27].…”

Section: Introductionmentioning

confidence: 99%

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The role of the MAD2-TLR4-MyD88 axis in paclitaxel resistance in ovarian cancer

et al. 2020

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Despite the use of front-line anticancer drugs such as paclitaxel for ovarian cancer treatment, mortality rates have remained almost unchanged for the past three decades and the majority of patients will develop recurrent chemoresistant disease which remains largely untreatable. Overcoming chemoresistance or preventing its onset in the first instance remains one of the major challenges for ovarian cancer research. In this study, we demonstrate a key link between senescence and inflammation and how this complex network involving the biomarkers MAD2, TLR4 and MyD88 drives paclitaxel resistance in ovarian cancer. This was investigated using siRNA knockdown of MAD2, TLR4 and MyD88 in two ovarian cancer cell lines, A2780 and SKOV-3 cells and overexpression of MyD88 in A2780 cells. Interestingly, siRNA knockdown of MAD2 led to a significant increase in TLR4 gene expression, this was coupled with the development of a highly paclitaxel-resistant cell phenotype. Additionally, siRNA knockdown of MAD2 or TLR4 in the serous ovarian cell model OVCAR-3 resulted in a significant increase in TLR4 or MAD2 expression respectively. Microarray analysis of SKOV-3 cells following knockdown of TLR4 or MAD2 highlighted a number of significantly altered biological processes including EMT, complement, coagulation, proliferation and survival, ECM remodelling, olfactory receptor signalling, ErbB signalling, DNA packaging, Insulin-like growth factor signalling, ion transport and alteration of components of the cytoskeleton. Cross comparison of the microarray data sets identified 7 overlapping genes including MMP13, ACTBL2, AMTN, PLXDC2, LYZL1, CCBE1 and CKS2. These results demonstrate an important link between these biomarkers, which to our knowledge has never before been shown in ovarian cancer. In the future, we hope that triaging patients into alterative treatment groups based on the expression of these three biomarkers or therapeutic targeting of the mechanisms they are involved in will lead to improvements in patient outcome and prevent the development of chemoresistance.

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“…Interestingly, in TGCTs patients, the overexpression of endogenous MAD2γ, but not MAD2α, was associated with resistance to cisplatin-based chemotherapy [ 108 , 109 ]. Since Nek2 interacts with MAD2 [ 110 ] and SAC has emerged as a promising target for cancer therapy [ 111 ], modulation of NEK2 activity and/or MAD2 AS could be exploited therapeutically in TGCTs patients displaying resistance to cisplatin-based chemotherapy. Accordingly, it has been shown that depletion of MAD2 induces apoptosis and restores sensitivity to cisplatin therapy in a cisplatin resistant lung cancer model [ 112 ].…”

Section: Rna Splicingmentioning

confidence: 99%

Non-Coding RNAs and Splicing Activity in Testicular Germ Cell Tumors

Barchi

Bielli

Dolci

et al. 2021

Life

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Testicular germ cell tumors (TGCTs) are the most common tumors in adolescent and young men. Recently, genome-wide studies have made it possible to progress in understanding the molecular mechanisms underlying the development of tumors. It is becoming increasingly clear that aberrant regulation of RNA metabolism can drive tumorigenesis and influence chemotherapeutic response. Notably, the expression of non-coding RNAs as well as specific splice variants is deeply deregulated in human cancers. Since these cancer-related RNA species are considered promising diagnostic, prognostic and therapeutic targets, understanding their function in cancer development is becoming a major challenge. Here, we summarize how the different expression of RNA species repertoire, including non-coding RNAs and protein-coding splicing variants, impacts on TGCTs’ onset and progression and sustains therapeutic resistance. Finally, the role of transcription-associated R-loop misregulation in the maintenance of genomic stability in TGCTs is also discussed.

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Too MAD or not MAD enough: The duplicitous role of the spindle assembly checkpoint protein MAD2 in cancer

Cited by 23 publications

References 94 publications

Targeting MAD2 modulates stemness and tumorigenesis in human Gastric Cancer cell lines

Targeting MAD2 modulates stemness and tumorigenesis in human Gastric Cancer cell lines

The role of the MAD2-TLR4-MyD88 axis in paclitaxel resistance in ovarian cancer

Non-Coding RNAs and Splicing Activity in Testicular Germ Cell Tumors

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