Calcium/calmodulin-dependent kinase II plays an important role in prostate cancer cell survival

Rokhlin, Oskar W.; Taghiyev, Agshin F.; Bayer, K. Ulrich; Bumcrot, David; Koteliansk, Victor E; Glover, Rebecca A.; Cohen, Michael B.

doi:10.4161/cbt.6.5.3975

Cited by 71 publications

(80 citation statements)

References 54 publications

(75 reference statements)

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“…As can be seen from Figure 3D, only KN-93 showed a dose-dependent inhibition of p53-Ser15 phosphorylation; there is some inhibition with STO-609, but only at high concetration (50 μM). We subsequently treated LNCaP-mock and LNCaP-CaMKII-β transfectant cells 17 with DOX in the presence of si-AR and found that CaMKII-β overexpression protected p53-Ser15 expression (Fig. 3E).…”

Section: Resultsmentioning

confidence: 98%

“…We also showed that the expression of CaMKII genes is under the control of AR. 17 As a first approach to investigate the potential role of CaMKII in AR-mediated inhibition of p53, we used a specific CaMKII inhibitor, KN-93, and a non-specific analog, KN-92, as a control. In addition, we used STO-609, which is an inhibitor of CaMK-kinase and its two major downstream targets CaMKI and CaMKIV, 28 as well as an inhibitor of p38 kinase, SB202190.…”

Section: Resultsmentioning

confidence: 99%

“…The potent siRNA AR (Si-AR; sense, 5'-CUGGGAAAGUCAAGCCCA-UTT-3'; antisense, 5'-AUGGGCUUGACUUUCCCAGTT-3') was as previously described. 17 To silence AR in LNCaP cells, si-AR was incorporated into cationic liposomal particles as described, 20 and added directly to culture medium at a final siRNA concentration of 50-100 nM. The expression of endogenous SPAK was inhibited by infection with recombinant lentivirus constructs pLSL-puro expressing siRNA hairpin under control of the RNA H1 promoter.…”

Section: Methodsmentioning

confidence: 99%

“…We also showed that the expression of CaMKII genes is under AR control: active AR in the presence of androgens inhibits CaMKII gene expression whereas inhibition of AR activity results in an elevated level of kinase activity and in enhanced expression of CaMKII-β and -γ genes. 17 This in turn activates the anti-apoptotic PI3K/Akt pathways. This may therefore be a mechanism by which prostate cancer cells escape apoptosis after knocking down AR expression.…”

Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

“…[13][14][15][16] However, we have recently found that knocking down AR expression by si-AR resulted in inhibition of caspase activity induced by wortmannin, an inhibitor of the PI3K/ Akt pathway. 17 An unexplained aspect is that while si-AR can itself induce caspase activity and cell death after treatment for 7-10 days, short term treatment (two days) with si-AR acts as an anti-apoptotic agent. The explanation for this came from experiments that showed inhibition of AR activated calcium/calmodulin-dependent kinase II (CaMKII); CaMKII phosphorylates (activates) the anti-apoptotic protein Akt by a PI3K-independent pathway.…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate cancer

Rokhlin¹,

Scheinker²,

Taghiyev³

et al. 2008

Cancer Biology & Therapy

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140

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We investigated whether knocking down AR expression effects apoptosis after treatment with different apoptosis-inducing agents. We found that siRNA AR (si-AR) significantly decreased apoptosis induced by topoisomerase inhibitors doxorubicin (DOX) and camptothecin (Campt). It is known that DNA double-strand break inducing agents leads to activation (phosphorylation) of p53 that in turn regulates the expression of a variety of apoptosis-related genes including microRNA(miR)-34a and 34b/c. We found that DOX induced five phosphorylation sites of p53 (Ser15, 20, 37, 46 and 392); all of these sites were inhibited by si-AR. Subsequently we identified three kinases, SPAK, MDC1 and CaMKII that are under AR control and two of them, MDC1 and CaMKII, apparently participate in p53 upstream events that resulted in p53 inhibition. Using qPCR we showed that the level of miR-34a increased by 3-fold after DOX, but no increase was found with si-AR. MiR-34c expression increased 27 fold after DOX and only by 2.7 times with si-AR. It appears that AR-dependent inhibition of p53 resulted in suppression of miR-34a and -34c expression. Importantly, DOX did not induce miR-34 in LNCaP grown in an androgen free medium or in AR-negative prostate cancer cell lines, DU145 and PC3. To directly investigate the role of miR-34 in DOX-mediated apoptosis, we transfected cells with anti-miR-34 oligonucleotides or with miR-34. We found that inhibition of individual miR-34, either 34a or 34c, or forced overexpression of miR-34a or miR-34c did not modulate DOX-mediated apoptosis. Only simultaneous inhibition or forced overexpression of both miR-34 resulted in modulation of DOX-mediated apoptosis. Taken together, our data indicate that cooperation between miR-34a and 34c plays an important role in AR-dependent p53-mediated apoptosis in prostate cancer.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate cancer

Rokhlin¹,

Scheinker²,

Taghiyev³

et al. 2008

Cancer Biology & Therapy

Self Cite

140

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TRPM4 regulates Akt/GSK3‐β activity and enhances β‐catenin signaling and cell proliferation in prostate cancer cells

Sagredo

Cappelli

et al. 2017

Molecular Oncology

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Increased expression of the TRPM4 channel has been reported to be associated with the progression of prostate cancer. However, the molecular mechanism underlying its effect remains unknown. This work found that decreasing TRPM4 levels leads to the reduced proliferation of PC3 cells. This effect was associated with a decrease in total β‐catenin protein levels and its nuclear localization, and a significant reduction in Tcf/Lef transcriptional activity. Moreover, TRPM4 silencing increases the Ser33/Ser37/Thr41 β‐catenin phosphorylated population and reduces the phosphorylation of GSK‐3β at Ser9, suggesting an increase in β‐catenin degradation as the underlying mechanism. Conversely, TRPM4 overexpression in LNCaP cells increases the Ser9 inhibitory phosphorylation of GSK‐3β and the total levels of β‐catenin and its nonphosphorylated form. Finally, PC3 cells with reduced levels of TRPM4 showed a decrease in basal and stimulated phosphoactivation of Akt1, which is likely responsible for the decrease in GSK‐3β activity in these cells. Our results also suggest that the effect of TRPM4 on Akt1 is probably mediated by an alteration in the calcium/calmodulin‐EGFR axis, linking TRPM4 activity with the observed effects in β‐catenin‐related signaling pathways. These results suggest a role for TRPM4 channels in β‐catenin oncogene signaling and underlying mechanisms, highlighting this ion channel as a new potential target for future therapies in prostate cancer.

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Calmodulin Inhibitors from Aspergillus stromatoides

González-Andrade

Valle

Macías-Rubalcava

et al. 2013

Chemistry & Biodiversity

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An organic extract was prepared from the culture medium and mycelia of the marine fungus Aspergillus stromatoides RAPER & FENNELL. The extract was fractionated via column chromatography, and the resulting fractions were tested for their abilities to quench the fluorescence of the calmodulin (CaM) biosensor hCaM M124C-mBBr. From the active fraction, emodin (1) and ω-hydroxyemodin (2) were isolated as CaM inhibitors. Anthraquinones 1 and 2 quenched the fluorescence of the hCaM M124C-mBBr biosensor in a concentration-dependent manner with K(d) values of 0.33 and 0.76 μM, respectively. The results were compared with those of chlorpromazine (CPZ), a classical inhibitor of CaM, with a K(d) value of 1.25 μM. Docking analysis revealed that 1 and 2 bind to the same pocket of CPZ. The CaM inhibitor properties of 1 and 2 were correlated with some of their reported biological properties. Citrinin (3), methyl 8-hydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate (4), and coniochaetone A (5) were also isolated in the present study. The X-ray structure of 5 is reported for the first time.

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Calcium/calmodulin-dependent kinase II plays an important role in prostate cancer cell survival

Cited by 71 publications

References 54 publications

MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate cancer

MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate cancer

TRPM4 regulates Akt/GSK3‐β activity and enhances β‐catenin signaling and cell proliferation in prostate cancer cells

Calmodulin Inhibitors from Aspergillus stromatoides

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