Regulation of Cdk7 activity through a phosphatidylinositol (3)-kinase/PKC- -mediated signaling cascade in glioblastoma

Desai, Shraddha; Pillai, Prajit; Patel, Rekha; McCray, Andrea N.; Win-Piazza, Hla; Acevedo‐Duncan, Mildred

doi:10.1093/carcin/bgr231

Cited by 22 publications

(23 citation statements)

References 44 publications

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“…In addition, TAM treatment did not induce an increase in the number of cells that underwent G2/M arrest subsequent to radiation exposure, but delayed the recovery of cell cycle progression. The activity of PKC-ι signaling, which plays an important role in the proliferation, apoptosis and cell cycle regulation of glioma cells (27,28,30), was markedly suppressed by TAM.…”

Section: Discussionmentioning

confidence: 98%

“…A synergistic effect of TAM with radiation in C6 glioma cells has been demonstrated, and may partially be due to the inhibition of PKC activation (18). The atypical PKC family member, PKC-ι was of particular interest as it is a key regulator of cell survival, proliferation, invasion and chemoresistance in glioma (27,30,34,35). The present results revealed an inhibitory role of TAM in the expression levels of p-PKC-ι, which may participate in the radioresistance of glioma cells.…”

Section: Discussionmentioning

confidence: 99%

“…PKC-ι may play an equivalent role in A172 and U251 cells, since inhibition of PKC-ι by TAM was revealed to increase the expression of Bad. In metazoans, the only known CDK-activating kinase is Cdk7 (36), which was revealed to be phosphorylated by PKC-ι in a cell cycle dependent manner (27,37). Inhibiting Cdk7 in the G2 phase blocks entry into mitosis and disrupts Cdk1/cyclin B complex assembly (38).…”

Section: Discussionmentioning

confidence: 99%

“…PKC-ι has been demonstrated to promote survival and prevent apoptosis in non-small-cell lung cancer and gastric carcinoma (25,26), and is highly activated and overexpressed in glioma. The kinase also plays a key role in cell cycle progression and proliferation (27,28). These findings indicated that PKC-ι is overexpressed in the hyper-proliferative state of gliomas, and is also associated with the resistance of gliomas to apoptosis in response to treatment with cytotoxic agents or ionizing radiation.…”

Section: Introductionmentioning

confidence: 91%

“…4). In addition, PKC-ι may phosphorylate Cdk7 in a cell cycle-dependent manner (27). As shown in Fig.…”

Section: Tam Suppressed the Activation Of Pkc-ι Signalingmentioning

confidence: 99%

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Radiosensitization of human glioma cells by tamoxifen is associated with the inhibition of PKC-ι activity in vitro

et al. 2015

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Abstract. The present study aimed to investigate the radiosensitizing effects of tamoxifen (TAM), a non-steroidal anti-estrogen drug, in human glioma A172 and U251 cells in vitro. A colony-forming assay revealed that TAM enhances radiosensitivity in A172 and U251 cells. Treatment with TAM also increased the percentage of apoptotic cells subsequent to ionizing radiation, and increased the expression of apoptotic markers, including cleaved caspase-3 and poly(ADP-ribose) polymerase. Ionizing radiation induced G2/M phase arrest, which was alleviated within 24 h when the radiation-induced DNA damage was repaired. However, flow cytometry analysis revealed that TAM treatment delayed the recovery of cell cycle progression. Additional examination demonstrated that TAM-mediated protein kinase C-ι (PKC-ι) inhibition may lead to the activation of pro-apoptotic B-cell lymphoma 2-associated death promoter, and the dephosphorylation of cyclin-dependent kinase 7, resulting in increased cell apoptosis and sustained G2/M phase arrest following exposure to radiation. The present data indicate that the radiosensitizing effects of TAM on glioma cells are partly due to the inhibition of PKC-ι activity in vitro.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

“…4). In addition, PKC-ι may phosphorylate Cdk7 in a cell cycle-dependent manner (27). As shown in Fig.…”

Section: Tam Suppressed the Activation Of Pkc-ι Signalingmentioning

confidence: 99%

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Radiosensitization of human glioma cells by tamoxifen is associated with the inhibition of PKC-ι activity in vitro

et al. 2015

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CDK7 inhibitors as anticancer drugs

Sava

Fan

Coombes

et al. 2020

Cancer Metastasis Rev

138

115

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Cyclin-dependent kinase 7 (CDK7), along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs progression through the cell cycle via T-loop phosphorylation of cell cycle CDKs. CAK is also a component of the general transcription factor, TFIIH. CDK7-mediated phosphorylation of RNA polymerase II (Pol II) at active gene promoters permits transcription. Cell cycle dysregulation is an established hallmark of cancer, and aberrant control of transcriptional processes, through diverse mechanisms, is also common in many cancers. Furthermore, CDK7 levels are elevated in a number of cancer types and are associated with clinical outcomes, suggestive of greater dependence on CDK7 activity, compared with normal tissues. These findings identify CDK7 as a cancer therapeutic target, and several recent publications report selective CDK7 inhibitors (CDK7i) with activity against diverse cancer types. Preclinical studies have shown that CDK7i cause cell cycle arrest, apoptosis and repression of transcription, particularly of super-enhancer-associated genes in cancer, and have demonstrated their potential for overcoming resistance to cancer treatments. Moreover, combinations of CDK7i with other targeted cancer therapies, including BET inhibitors, BCL2 inhibitors and hormone therapies, have shown efficacy in model systems. Four CDK7i, ICEC0942 (CT7001), SY-1365, SY-5609 and LY3405105, have now progressed to Phase I/II clinical trials. Here we describe the work that has led to the development of selective CDK7i, the current status of the most advanced clinical candidates, and discuss their potential importance as cancer therapeutics, both as monotherapies and in combination settings. ClinicalTrials.gov Identifiers: NCT03363893; NCT03134638; NCT04247126; NCT03770494.

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The Interruption of PKC-ι Signaling and TRAIL Combination Therapy Against Glioblastoma Cells

2014

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Glioblastoma is a highly aggressive type of brain cancer which currently has limited options for treatment. It is imperative to develop combination therapies that could cause apoptosis in glioblastoma. The aim of this study was to characterize the affect of modified ICA-1, a PKC-iota inhibitor, on the growth pattern of various glioblastoma cell lines. T98G and U87 glioblastoma cells were treated with ICA-1 alone and the absolute cell numbers of each group were determined for cell growth expansion analysis, cell viability analysis, and cell death analysis. Low dose ICA-1 treatment alone significantly inhibited cell growth expansion of high density glioblastoma cells without inducing cell death. However, the high dose ICA-1 treatment regimen provided significant apoptosis for glioblastoma cells. Furthermore, this study was conducted to use a two layer molecular level approach for treating glioblastoma cells with ICA-1 plus an apoptosis agent, tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL), to induce apoptosis in such chemo-refractory cancer cells. Following ICA-1 plus TRAIL treatment, apoptosis was detected in glioblastoma cells via the TUNEL assay and via flow cytometric analysis using Annexin-V FITC/PI. This study offers the first evidence for ICA-1 alone to inhibit glioblastoma cell proliferation as well as the novel combination of ICA-1 with TRAIL to cause robust apoptosis in a caspase-3 mediated mechanism. Furthermore, ICA-1 plus TRAIL simultaneously modulates down-regulation of PKC-iota and c-Jun.

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Regulation of Cdk7 activity through a phosphatidylinositol (3)-kinase/PKC- -mediated signaling cascade in glioblastoma

Cited by 22 publications

References 44 publications

Radiosensitization of human glioma cells by tamoxifen is associated with the inhibition of PKC-ι activity in vitro

Radiosensitization of human glioma cells by tamoxifen is associated with the inhibition of PKC-ι activity in vitro

CDK7 inhibitors as anticancer drugs

The Interruption of PKC-ι Signaling and TRAIL Combination Therapy Against Glioblastoma Cells

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