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Published on: May 14, 2016
Inhibition of Cdk5 induces cell death of tumor-initiating cells
Melanie M Mandl1, Siwei Zhang1, Melanie Ulrich1
1Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-University of Munich (LMU), Butenandtstr 5-13, Munich 81377, Germany.
Background:
Tumour-initiating cells (TICs) account for chemoresistance, tumour recurrence and metastasis, and therefore represent a major problem in tumour therapy. However, strategies to address TICs are limited. Recent studies indicate Cdk5 as a promising target for anti-cancer therapy and Cdk5 has recently been associated with epithelial-mesenchymal transition (EMT). However, a role of Cdk5 in TICs has not been described yet.
Methods:
Expression of Cdk5 in human cancer tissue was analysed by staining of a human tissue microarray (TMA). Functional effects of Cdk5 overexpression, genetic knockdown by siRNA and shRNA, and pharmacologic inhibition by the small molecule roscovitine were tested in migration, invasion, cell death, and tumorsphere assays and in tumour establishment in vivo. For mechanistic studies, molecular biology methods were applied.
Results:
In fact, here we pin down a novel function of Cdk5 in TICs: knockdown and pharmacological inhibition of Cdk5 impaired tumorsphere formation and reduced tumour establishment in vivo. Conversely, Cdk5 overexpression promoted tumorsphere formation which was in line with increased expression of Cdk5 in human breast cancer tissues as shown by staining of a human TMA. In order to understand how Cdk5 inhibition affects tumorsphere formation, we identify a role of Cdk5 in detachment-induced cell death: Cdk5 inhibition induced apoptosis in tumorspheres by stabilizing the transcription factor Foxo1 which results in increased levels of the pro-apoptotic protein Bim.
Conclusions:
In summary, our study elucidates a Cdk5-Foxo1-Bim pathway in cell death in tumorspheres and suggests Cdk5 as a potential target to address TICs.
Insights
Cyclin-dependent kinase 5 (Cdk5) plays a key role in tumour-initiating cells (TICs), promoting their survival and tumour formation. Inhibiting Cdk5 induces apoptosis in TICs by activating a Cdk5-Foxo1-Bim pathway, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Tumour-initiating cells (TICs) are responsible for chemoresistance, recurrence, and metastasis, posing a significant challenge in cancer therapy.
- Current strategies to target TICs are limited.
- Cyclin-dependent kinase 5 (Cdk5) is emerging as a potential anti-cancer target, with recent links to epithelial-mesenchymal transition (EMT), but its role in TICs remains unexplored.
Purpose of the Study:
- To investigate the role of Cdk5 in tumour-initiating cells (TICs).
- To explore the potential of Cdk5 as a therapeutic target for addressing TICs.
Main Methods:
- Analysis of Cdk5 expression in human breast cancer tissues using tissue microarrays (TMA).
- Functional assays including tumorsphere formation, migration, invasion, and cell death assays.
- In vivo tumour establishment studies.
- Genetic manipulation (siRNA, shRNA) and pharmacological inhibition (roscovitine) of Cdk5.
- Molecular biology techniques for mechanistic studies.
Main Results:
- Cdk5 knockdown and inhibition significantly impaired tumorsphere formation and reduced in vivo tumour establishment.
- Cdk5 overexpression promoted tumorsphere formation, correlating with increased Cdk5 expression in human breast cancer.
- Cdk5 inhibition induced apoptosis in tumorspheres by stabilizing Foxo1, leading to increased Bim levels, thus uncovering a Cdk5-Foxo1-Bim pathway.
Conclusions:
- The study identifies a novel Cdk5-Foxo1-Bim pathway crucial for regulating cell death in tumorspheres.
- Cdk5 is implicated as a key regulator of tumour-initiating cells.
- Cdk5 represents a promising therapeutic target for overcoming chemoresistance and preventing tumour recurrence and metastasis.
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