Tropomyosin as a Regulator of Cancer Cell Transformation

Helfman, David M.; Flynn, Patrick; Khan, Protiti; Saeed, Ali

doi:10.1007/978-0-387-85766-4_10

Cited by 60 publications

(55 citation statements)

References 55 publications

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“…TPM1 is an actin-binding protein (32), which belongs to the cytoskeleton regulation pathways. It has two UGCAUG binding motifs within the 200 bp flanking exons 6a and 6b, which are spliced mutually exclusively (33).…”

Section: Resultsmentioning

confidence: 99%

Neutralization of terminal differentiation in gliomagenesis

Yuan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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An immature state of cellular differentiation-characterized by stem cell-like tendencies and impaired differentiation-is a hallmark of cancer. Using glioblastoma multiforme (GBM) as a model system, we sought to determine whether molecular determinants that drive cells toward terminal differentiation are also genetically targeted in carcinogenesis and whether neutralizing such genes also plays an active role to reinforce the impaired differentiation state and promote malignancy. To that end, we screened 71 genes with known roles in promoting nervous system development that also sustain copy number loss in GBM through antineoplastic assay and identified A2BP1 (ataxin 2 binding protein 1, Rbfox1), an RNAbinding and splicing regulator that is deleted in 10% of GBM cases. Integrated in silico analysis of GBM profiles to elucidate the A2BP1 pathway and its role in glioma identified myelin transcription factor 1-like (Myt1L) as a direct transcriptional regulator of A2BP1. Reintroduction of A2BP1 or Myt1L in GBM cell lines and glioma stem cells profoundly inhibited tumorigenesis in multiple assays, and conversely, shRNA-mediated knockdown of A2BP1 or Myt1L in premalignant neural stem cells compromised neuronal lineage differentiation and promoted orthotopic tumor formation. On the mechanistic level, with the top-represented downstream target TPM1 as an illustrative example, we demonstrated that, among its multiple functions, A2BP1 serves to regulate TPM1's alternative splicing to promote cytoskeletal organization and terminal differentiation and suppress malignancy. Thus, in addition to the activation of self-renewal pathways, the neutralization of genetic programs that drive cells toward terminal differentiation may also promote immature and highly plastic developmental states that contribute to the aggressive malignant properties of GBM.oncogenomics | cancer stem cells

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Section: Resultsmentioning

confidence: 99%

Neutralization of terminal differentiation in gliomagenesis

Yuan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The actin cytoskeleton has long been regarded as an attractive target for cancer therapy, but the intolerable cardiotoxicity associated with targeting actin has resulted in a lack of antiactin agents passing through animal toxicity (4)(5)(6)(7)(8). In metazoans, actin filaments are usually formed as a copolymer with tropomyosin where the particular isoform of tropomyosin defines the functional properties of the filament (9).…”

Section: Introductionmentioning

confidence: 99%

Identification of Cancer-Targeted Tropomyosin Inhibitors and Their Synergy with Microtubule Drugs

Currier

Stehn

Swain

et al. 2017

Molecular Cancer Therapeutics

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Actin filaments, with their associated tropomyosin polymers, and microtubules are dynamic cytoskeletal systems regulating numerous cell functions. While antimicrotubule drugs are wellestablished, antiactin drugs have been more elusive. We previously targeted actin in cancer cells by inhibiting the function of a tropomyosin isoform enriched in cancer cells, Tpm3.1, using a first-in-class compound, TR100. Here, we screened over 200 other antitropomyosin analogues for anticancer and ontarget activity using a series of in vitro cell-based and biochemical assays. ATM-3507 was selected as the new lead based on its ability to disable Tpm3.1-containing filaments, its cytotoxicity potency, and more favorable drug-like characteristics. We tested ATM-3507 and TR100 alone and in combination with antimicrotubule agents against neuroblastoma models in vitro and in vivo. Both ATM-3507 and TR100 showed a high degree of synergy in vitro with vinca alkaloid and taxane antimicrotubule agents. In vivo, combination-treated animals bearing human neuroblastoma xenografts treated with antitropomyosin combined with vincristine showed minimal weight loss, a significant and profound regression of tumor growth and improved survival compared with control and either drug alone. Antitropomyosin combined with vincristine resulted in G 2 -M phase arrest, disruption of mitotic spindle formation, and cellular apoptosis. Our data suggest that small molecules targeting the actin cytoskeleton via tropomyosin sensitize cancer cells to antimicrotubule agents and are tolerated together in vivo. This combination warrants further study.

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“…In the study, finally, six peptides were found to have a c o n s e n s u s a n d u s e d f o r i n s i l i c o c o n c a t e n a t i o n : A A 6 [32]. Comparison of homology models with the template proteins reveals similarities which allow biochemical and biological functions to be inferred.…”

Section: Prediction Of B and Cd4 + T Epitopesmentioning

confidence: 95%

“…This protein has interspecies conservation, binder, and actin regulator properties that are important in the contraction of muscles. It has also actin regulator activity and plays an important role in immune and allergic reactions [6]. TPM has been introduced as a vaccine candidate in several parasites [7], which causes cross-reactivity due to conservation.…”

Section: Introductionmentioning

confidence: 99%

Designing and Modeling of Complex DNA Vaccine Based on Tropomyosin Protein of Boophilus Genus Tick

Ranjbar

Gupta

Ghorban

et al. 2014

Appl Biochem Biotechnol

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Boophilus tick is a bloodsucking ectoparasite that transfers some pathogens, reducing production and thus leading to economical losses in the cattle industry. Tropomyosin (TPM) protein is a salivary protein, has actin regulator activity, and plays an important role in immune reactions against parasites. In the current study, besides developing a safe, effective, and broad spectrum protective measure against Boophilus genus tick based on TPM protein, we attempted to minimize possible problems occurring in the design of polytopic vaccines. Briefly, the steps that were followed in the present study were as follows: retrieving sequences and finding the mutational/conservative regions, selecting consensus and high immunogenic epitopes of B and CD4(+) T cells by different approaches, three-dimensional structure (3D structure) prediction and representation of epitopes and highly variable/conserve regions, designing vaccinal construct by fusion of B and T cell epitopes by special patterns and improving immunogenicity, evaluation of the constructs' primary structure and posttranslational modification, calculation of hydrophobic regions, reverse translation, codon optimization, open reading frame checking, insertion of start/end codon, Kozak sequence, and finally constructing the DNA vaccine. Variation plot showed some shared epitopes among the ticks' and mites' species that some might be effective only in some species. Finally, by following the steps mentioned above, two constructs for B and T cells were achieved. Checking constructs revealed their reliability and efficacy for in vitro production and utilization. Successful in silico modeling is an essential step of designing vigorous vaccines. We developed a novel protective and therapeutic vaccine against Boophilus genus (based on TPM protein). At the next step, constructed DNA vaccine would be produced in vitro and administrated to cattle, and its potency to induction of immune response and protection against Boophilus genus as well as other ticks and mites will be evaluated.

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Tropomyosin as a Regulator of Cancer Cell Transformation

Cited by 60 publications

References 55 publications

Neutralization of terminal differentiation in gliomagenesis

Neutralization of terminal differentiation in gliomagenesis

Identification of Cancer-Targeted Tropomyosin Inhibitors and Their Synergy with Microtubule Drugs

Designing and Modeling of Complex DNA Vaccine Based on Tropomyosin Protein of Boophilus Genus Tick

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