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  1. Article ; Online: Effect of caldesmon mutations in the development of zebrafish embryos.

    Virtanen, Verneri / Paunu, Kreetta / Niva, Saana / Sundvall, Maria / Paatero, Ilkka

    Biochemical and biophysical research communications

    2023  Volume 669, Page(s) 10–18

    Abstract: Cancer is a profound medical concern and better treatments are needed for cancer patients. Therefore, new cancer targets are constantly being studied. These targets need not only be relevant for cancer progression, but their modulation needs to be ... ...

    Abstract Cancer is a profound medical concern and better treatments are needed for cancer patients. Therefore, new cancer targets are constantly being studied. These targets need not only be relevant for cancer progression, but their modulation needs to be tolerated reasonably well by the host. Caldesmon is one of these proposed novel targets for cancer therapy. Therefore, we analyzed effects of caldesmon mutations in normal development using genetically modified zebrafish embryos. We analyzed mutations in both zebrafish caldesmon genes, cald1a and cald1b and analyzed effects of either mutation alone or as in combination in double homozygous embryos using molecular, morphological and functional analyses. The effects of caldesmon mutations were mild and the gross development of zebrafish embryos was normal. The caldesmon mutant embryos had, however, alterations in response to light-stimulus in behavioural assays. Taken together, the effects of caldesmon mutations in the development of zebrafish embryos were reasonably well tolerated and did not indicate significant concerns for caldesmon being a potential target for cancer therapy.
    MeSH term(s) Animals ; Zebrafish/metabolism ; Calmodulin-Binding Proteins/genetics ; Mutation ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
    Chemical Substances Calmodulin-Binding Proteins ; Zebrafish Proteins
    Language English
    Publishing date 2023-05-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 205723-2
    ISSN 1090-2104 ; 0006-291X ; 0006-291X
    ISSN (online) 1090-2104 ; 0006-291X
    ISSN 0006-291X
    DOI 10.1016/j.bbrc.2023.05.079
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Glucocorticoid receptor-induced non-muscle caldesmon regulates metastasis in castration-resistant prostate cancer.

    Virtanen, Verneri / Paunu, Kreetta / Kukkula, Antti / Niva, Saana / Junila, Ylva / Toriseva, Mervi / Jokilehto, Terhi / Mäkelä, Sari / Huhtaniemi, Riikka / Poutanen, Matti / Paatero, Ilkka / Sundvall, Maria

    Oncogenesis

    2023  Volume 12, Issue 1, Page(s) 42

    Abstract: Lethal prostate cancer (PCa) is characterized by the presence of metastases and development of resistance to therapies. Metastases form in a multi-step process enabled by dynamic cytoskeleton remodeling. An actin cytoskeleton regulating gene, CALD1, ... ...

    Abstract Lethal prostate cancer (PCa) is characterized by the presence of metastases and development of resistance to therapies. Metastases form in a multi-step process enabled by dynamic cytoskeleton remodeling. An actin cytoskeleton regulating gene, CALD1, encodes a protein caldesmon (CaD). Its isoform, low-molecular-weight CaD (l-CaD), operates in non-muscle cells, supporting the function of filaments involved in force production and mechanosensing. Several factors, including glucocorticoid receptor (GR), have been identified as regulators of l-CaD in different cell types, but the regulation of l-CaD in PCa has not been defined. PCa develops resistance in response to therapeutic inhibition of androgen signaling by multiple strategies. Known strategies include androgen receptor (AR) alterations, modified steroid synthesis, and bypassing AR signaling, for example, by GR upregulation. Here, we report that in vitro downregulation of l-CaD promotes epithelial phenotype and reduces spheroid growth in 3D, which is reflected in vivo in reduced formation of metastases in zebrafish PCa xenografts. In accordance, CALD1 mRNA expression correlates with epithelial-to-mesenchymal transition (EMT) transcripts in PCa patients. We also show that CALD1 is highly co-expressed with GR in multiple PCa data sets, and GR activation upregulates l-CaD in vitro. Moreover, GR upregulation associates with increased l-CaD expression after the development of resistance to antiandrogen therapy in PCa xenograft mouse models. In summary, GR-regulated l-CaD plays a role in forming PCa metastases, being clinically relevant when antiandrogen resistance is attained by the means of bypassing AR signaling by GR upregulation.
    Language English
    Publishing date 2023-08-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2674437-5
    ISSN 2157-9024
    ISSN 2157-9024
    DOI 10.1038/s41389-023-00485-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: PARP Inhibitors in Prostate Cancer—The Preclinical Rationale and Current Clinical Development.

    Virtanen, Verneri / Paunu, Kreetta / Ahlskog, Johanna K / Varnai, Reka / Sipeky, Csilla / Sundvall, Maria

    Genes

    2019  Volume 10, Issue 8

    Abstract: Prostate cancer is globally the second most commonly diagnosed cancer type in men. Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms of prostate cancer and castration resistance. Prostate cancer with DNA ... ...

    Abstract Prostate cancer is globally the second most commonly diagnosed cancer type in men. Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms of prostate cancer and castration resistance. Prostate cancer with DNA repair defects may be vulnerable to therapeutic targeting by Poly(ADP-ribose) polymerase (PARP) inhibitors. PARP enzymes modify target proteins with ADP-ribose in a process called PARylation and are in particular involved in single strand break repair. The rationale behind the clinical trials that led to the current use of PARP inhibitors to treat cancer was to target the dependence of BRCA-mutant cancer cells on the PARP-associated repair pathway due to deficiency in homologous recombination. However, recent studies have proposed therapeutic potential for PARP inhibitors in tumors with a variety of vulnerabilities generating dependence on PARP beyond the synthetic lethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initially thought. Importantly, PARP-associated DNA repair pathways are also closely connected to androgen receptor (AR) signaling, which is a key regulator of tumor growth and a central therapeutic target in prostate cancer. In this review, we provide an extensive overview of published and ongoing trials exploring PARP inhibitors in treatment of prostate cancer and discuss the underlying biology. Several clinical trials are currently studying PARP inhibitor mono- and combination therapies in the treatment of prostate cancer. Integration of drugs targeting DNA repair pathways in prostate cancer treatment modalities allows developing of more personalized care taking also into account the genetic makeup of individual tumors.
    MeSH term(s) Animals ; Antineoplastic Agents/therapeutic use ; Clinical Trials as Topic ; Drug Evaluation, Preclinical ; Humans ; Male ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Poly(ADP-ribose) Polymerases/genetics ; Poly(ADP-ribose) Polymerases/metabolism ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism
    Chemical Substances Antineoplastic Agents ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30)
    Language English
    Publishing date 2019-07-26
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2527218-4
    ISSN 2073-4425 ; 2073-4425
    ISSN (online) 2073-4425
    ISSN 2073-4425
    DOI 10.3390/genes10080565
    Database MEDical Literature Analysis and Retrieval System OnLINE

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