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Cyclin-Dependent Kinase 5 (CDK5) Controls Melanoma Cell Motility, Invasiveness, and Metastatic Spread-Identification of a Promising Novel therapeutic target.

Bisht S, Nolting J, Schütte U, Haarmann J, Jain P, Shah D, Brossart P, Flaherty P, Feldmann G - Transl Oncol (2015)

Bottom Line: In vivo, CDK5 knockdown inhibited growth of orthotopic xenografts as well as formation of lung and liver colonies in xenogenic injection models mimicking systemic metastases.CDK5 knockdown was accompanied by dephosphorylation and overexpression of caldesmon, and concomitant caldesmon knockdown rescued cell motility and proinvasive phenotype.Finally, it was found that pharmacological inhibition of CDK5 activity by means of roscovitine as well as by a novel small molecule CDK5-inhibitor, N-(5-isopropylthiazol-2-yl)-3-phenylpropanamide, similarly caused marked inhibition of invasion/migration, colony formation, and anchorage-independent growth of melanoma cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine 3, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Germany.

No MeSH data available.


Related in: MedlinePlus

Therapeutic in vitro efficacy testing of pharmacological inhibition of CDK5 activity. (A) MTS assays do not show any reduction in cell viability after 72 hours upon incubation with up to 10 μM roscovitine or PJB. (B) Reduction of invasion/migration in modified Boyden chamber assays and of (C) colony formation and anchorage-independent growth in soft agar assays upon CDK5 inhibition with roscovitine or PJB, respectively. (D) Small molecule CDK5 inhibitors roscovitine or PJB caused dephosphorylation of caldesmon, while not affecting total CDK5 protein levels as observed using Western blot analysis.
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f0040: Therapeutic in vitro efficacy testing of pharmacological inhibition of CDK5 activity. (A) MTS assays do not show any reduction in cell viability after 72 hours upon incubation with up to 10 μM roscovitine or PJB. (B) Reduction of invasion/migration in modified Boyden chamber assays and of (C) colony formation and anchorage-independent growth in soft agar assays upon CDK5 inhibition with roscovitine or PJB, respectively. (D) Small molecule CDK5 inhibitors roscovitine or PJB caused dephosphorylation of caldesmon, while not affecting total CDK5 protein levels as observed using Western blot analysis.

Mentions: Of note, and in line with data obtained from CDK5 knockdown experiments, CDK5 inhibition with roscovitine or PJB did not have any discernible effect on net cell viability as assessed using MTS assays at concentrations of up to 10 μM after up to 72 hours (Figure 8A).


Cyclin-Dependent Kinase 5 (CDK5) Controls Melanoma Cell Motility, Invasiveness, and Metastatic Spread-Identification of a Promising Novel therapeutic target.

Bisht S, Nolting J, Schütte U, Haarmann J, Jain P, Shah D, Brossart P, Flaherty P, Feldmann G - Transl Oncol (2015)

Therapeutic in vitro efficacy testing of pharmacological inhibition of CDK5 activity. (A) MTS assays do not show any reduction in cell viability after 72 hours upon incubation with up to 10 μM roscovitine or PJB. (B) Reduction of invasion/migration in modified Boyden chamber assays and of (C) colony formation and anchorage-independent growth in soft agar assays upon CDK5 inhibition with roscovitine or PJB, respectively. (D) Small molecule CDK5 inhibitors roscovitine or PJB caused dephosphorylation of caldesmon, while not affecting total CDK5 protein levels as observed using Western blot analysis.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4562979&req=5

f0040: Therapeutic in vitro efficacy testing of pharmacological inhibition of CDK5 activity. (A) MTS assays do not show any reduction in cell viability after 72 hours upon incubation with up to 10 μM roscovitine or PJB. (B) Reduction of invasion/migration in modified Boyden chamber assays and of (C) colony formation and anchorage-independent growth in soft agar assays upon CDK5 inhibition with roscovitine or PJB, respectively. (D) Small molecule CDK5 inhibitors roscovitine or PJB caused dephosphorylation of caldesmon, while not affecting total CDK5 protein levels as observed using Western blot analysis.
Mentions: Of note, and in line with data obtained from CDK5 knockdown experiments, CDK5 inhibition with roscovitine or PJB did not have any discernible effect on net cell viability as assessed using MTS assays at concentrations of up to 10 μM after up to 72 hours (Figure 8A).

Bottom Line: In vivo, CDK5 knockdown inhibited growth of orthotopic xenografts as well as formation of lung and liver colonies in xenogenic injection models mimicking systemic metastases.CDK5 knockdown was accompanied by dephosphorylation and overexpression of caldesmon, and concomitant caldesmon knockdown rescued cell motility and proinvasive phenotype.Finally, it was found that pharmacological inhibition of CDK5 activity by means of roscovitine as well as by a novel small molecule CDK5-inhibitor, N-(5-isopropylthiazol-2-yl)-3-phenylpropanamide, similarly caused marked inhibition of invasion/migration, colony formation, and anchorage-independent growth of melanoma cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine 3, Center of Integrated Oncology (CIO) Cologne-Bonn, University Hospital of Bonn, Germany.

No MeSH data available.


Related in: MedlinePlus