Lessons from border cell migration in the
            <i>Drosophila</i>
            ovary: A role for myosin VI in dissemination of human ovarian cancer

Yoshida, Hiroyuki; Cheng, Wenjun; Hung, Jamie; Montell, Denise J.; Geisbrecht, Erika R.; Rosen, Daniel; Liu, Jinsong; Naora, Honami

doi:10.1073/pnas.0400400101

Cited by 146 publications

(149 citation statements)

References 33 publications

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“…We find that miR-143 and miR-145 negatively regulate MYO6 and could prove this effect at the mRNA as well as at the protein level. Myosin VI in contrast to all other myosins is the only identified member of this protein family that is capable of moving toward the minus end of the actin filament (31) and is involved in cancer-related cell migration (32). The dramatic loss of both miR-143 and miR-145 in prostate cancer tissue establishes one molecular mechanism for the described increase in myosin VI protein levels in prostate cancer (22,33).…”

Section: Discussionmentioning

confidence: 98%

The MicroRNA Profile of Prostate Carcinoma Obtained by Deep Sequencing

Szczyrba

Löprich²,

Wach³

et al. 2010

Molecular Cancer Research

208

207

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Prostate cancer is a leading cause of tumor mortality. To characterize the underlying molecular mechanisms, we have compared the microRNA (miRNA) profile of primary prostate cancers and noncancer prostate tissues using deep sequencing. MiRNAs are small noncoding RNAs of 21 to 25 nucleotides that regulate gene expression through the inhibition of protein synthesis. We find that 33 miRNAs were upregulated or downregulated >1.5-fold. The deregulation of selected miRNAs was confirmed by both Northern blotting and quantitative reverse transcription-PCR in established prostate cancer cell lines and clinical tissue samples. A computational search indicated the 3′-untranslated region (UTR) of the mRNA for myosin VI (MYO6) as a potential target for both miR-143 and miR-145, the expression of which was reduced in the tumor tissues. Upregulation of myosin VI in prostate cancer was previously shown by immunohistochemistry. The level of MYO6 mRNA was significantly induced in all primary tumor tissues compared with the nontumor tissue from the same patient. This finding was matched to the upregulation of myosin VI in established prostate cancer cell lines. In luciferase reporter analysis, we find a significant negative regulatory effect on the MYO6 3′UTR by both miR-143 and miR-145. Mutation of the potential binding sites for miR-143 and miR-145 in the MYO6 3′ UTR resulted in a loss of responsiveness to the corresponding miRNA. Our data indicate that miR-143 and miR-145 are involved in the regulation of MYO6 expression and possibly in the development of prostate cancer. Mol Cancer Res; 8(4); 529-38. ©2010 AACR.

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Section: Discussionmentioning

confidence: 98%

The MicroRNA Profile of Prostate Carcinoma Obtained by Deep Sequencing

Szczyrba

Löprich²,

Wach³

et al. 2010

Molecular Cancer Research

208

207

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“…This allosteric binding site has thus the potential to guide the design of novel class-specific myosin inhibitors. In particular, myosin VI and myosin X are interesting pharmaceutical targets due to their recently established role in cell migration and metastasis (21)(22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

Highly selective inhibition of myosin motors provides the basis of potential therapeutic application

Sirigu

Hartman

Planelles-Herrero

et al. 2016

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

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Direct inhibition of smooth muscle myosin (SMM) is a potential means to treat hypercontractile smooth muscle diseases. The selective inhibitor CK-2018571 prevents strong binding to actin and promotes muscle relaxation in vitro and in vivo. The crystal structure of the SMM/drug complex reveals that CK-2018571 binds to a novel allosteric pocket that opens up during the "recovery stroke" transition necessary to reprime the motor. Trapped in an intermediate of this fast transition, SMM is inhibited with high selectivity compared with skeletal muscle myosin (IC 50 = 9 nM and 11,300 nM, respectively), although all of the binding site residues are identical in these motors. This structure provides a starting point from which to design highly specific myosin modulators to treat several human diseases. It further illustrates the potential of targeting transition intermediates of molecular machines to develop exquisitely selective pharmacological agents.M yosins comprise a family of ATP-dependent motor proteins capable of producing directed force via interaction with their track, the F-actin filament. Force production by these motors powers numerous cellular processes such as muscle contraction, intracellular transport, and cell migration and division (1). Several myosins have also been linked to genetic disorders where either gain or loss of motor function can lead to disease. These motor proteins represent promising targets for the development of drugs modulating force production in cells, tissues, and muscle (2-4). Here we report a selective, smallmolecule inhibitor of smooth muscle myosin (SMM) able to induce muscle relaxation. This mechanism of action has potential relevance for many diseases where smooth muscle contractility is central to the pathophysiology, such as asthma (5, 6) and chronic obstructive pulmonary disease (7).Smooth muscle contractility can be activated through different pathways. Existing airway smooth muscle relaxants, such as β-adrenergic agonists and muscarinic antagonists, ultimately inhibit the activity of SMM. However, they do so via specific upstream signaling pathways. Direct inhibition of SMM contractility has the advantage of relaxing contracted smooth muscle regardless of the molecular stimulus driving it. Moreover, application of SMM inhibitors to the airway provides a means of selectively modulating contractility of these tissues by delivering a high local concentration of drug. We thus set about identifying selective inhibitors of SMM that can effectively relax muscle in vivo, leading to the discovery of a highly selective, small-molecule inhibitor, CK-2018571 (CK-571).The detailed inhibitory mechanism of CK-571 was elucidated by a combination of in vitro characterization of the step in which the drug traps the motor and determination of the high-resolution structure of SMM cocrystallized with CK-571. The drug targets an intermediate state that occurs during the recovery stroke, the large conformational rearrangement that enables repriming of the motor. Blocking this critical transiti...

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“…An additional 100 ll of culture medium, without or with specified concentrations of rhEpo, paclitaxel, cisplatin or carboplatin were then dispensed into the appropriate wells. After incubation for specified times, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) (Sigma, St. Louis, MO) [10][11][12][13][14][15][16][17] was added to a final concentration of 0.2 mg/ml. After 4 hr of incubation at 37°C, 100 ll of 20% SDS in 0.01 N HCl were added to dissolve the MTT-formazan product, and the incubation was continued overnight.…”

Section: Cell Growth/survival Assaymentioning

confidence: 99%

Erythropoietin treatment of human ovarian cancer cells results in enhanced signaling and a paclitaxel‐resistant phenotype

Solár

Feldman

Jeong

et al. 2007

Intl Journal of Cancer

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Erythropoietin (Epo), a glycoprotein hormone that is the principal regulator of erythropoiesis, is known to act also on nonhematopoietic cell types. Epo receptors have been reported on several normal and neoplastic human cells and tissues, including ovarian cancer cells. We found that long-term Epo treatment of A2780 cells resulted in the development of a phenotype exhibiting both enhanced Epo signaling, evidenced by increased peak levels of phospho-Erk1/2 and increased paclitaxel resistance. This phenotypic effect was specific for paclitaxel, since no change in cisplatin or carboplatin sensitivity was observed. In addition, the change in phenotype was stable, even after the removal of Epo. Measurement of mono-and oligonucleosome formation revealed that longterm Epo treated A2780 cells exhibited markedly less apoptosis than nonerythropoietin treated cells at essentially all concentrations of paclitaxel tested. Western blot analyses revealed that the long-term Epo treated cells had significantly reduced expression of apoptosis-related proteins Bcl-2 and Bcl-10. These findings may have implications for the clinical use of recombinant human Epo and other erythropoiesis stimulating agents to correct anemia in paclitaxel-treated cancer patients. ' 2007 Wiley-Liss, Inc.Key words: erythropoietin; signaling; ovarian cancer; paclitaxel; chemoresistance; apoptosis Erythropoietin (Epo) is the prime regulator of erythroid cell growth and differentiation. Additionally, a wide variety of normal and malignant nonhematopoietic cells have been reported to express the Epo receptor (EpoR) and in some cases, Epo has been shown to act on these cells, sometimes as a survival/antiapoptotic factor (reviewed in Ref. 1).Reports of erythropoietin receptor (EpoR) expression by a variety of cancer cell types and the use of recombinant human erythropoietin (epoetin) and darbepoetin to treat anemia in cancer patients have raised concern regarding the potential for antiapoptotic effects of these erythropoiesis stimulating agents on the cancer itself. [2][3][4][5][6] Some clinical studies have proven especially worrisome. The Breast Cancer Erythropoietin Trial (BEST) was terminated early because of increased mortality in patients receiving Epo. 6 There was an increase in early disease progression. A trial of Epo in head and neck cancer patients treated with radiotherapy resulted in an increase in locoregional recurrence and a decrease in survival in the Epo-treated group. 5 Recently, a trial of darbepoetin to enhance radiosensitivity of head and neck cancer was stopped due to a significantly poorer outcome in the darbepoetin treatment group. 7,8 In an accompanying study, we show that each of 4 human ovarian cancer cell lines, including A2780, expresses both the EpoR and Epo at the mRNA and protein levels. Additionally, we show that these EpoR are functional in initiating Epo-dependent intracellular signaling and that an Epo/EpoR autocrine/ paracrine mechanism may be operative in enhancing ovarian cancer cell growth.In the present report, we ha...

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Lessons from border cell migration in the Drosophila ovary: A role for myosin VI in dissemination of human ovarian cancer

Cited by 146 publications

References 33 publications

The MicroRNA Profile of Prostate Carcinoma Obtained by Deep Sequencing

The MicroRNA Profile of Prostate Carcinoma Obtained by Deep Sequencing

Highly selective inhibition of myosin motors provides the basis of potential therapeutic application

Erythropoietin treatment of human ovarian cancer cells results in enhanced signaling and a paclitaxel‐resistant phenotype

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