Inhibition of Cdk5 induces cell death of tumor-initiating cells

Abstract

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.

Immune system‑associated genes increase malignant progression and can be used to predict clinical outcome in patients with hepatocellular carcinoma

“…Although CDK5 shares homologous structure with other CDKs, it is not cyclin-dependent and does not need to be phosphorylated in the T-loop for activation (66). CDK5 expression is upregulated in several types of cancer, and inhibition induces cancer cell death through a FOXO1-Bim pathway or mitochondrial dysfunction (67)(68)(69)(70)(71)(72)(73). Ehrlich et al (74) showed that expression of CDK5 was increased in HCC tissues, and was correlated with malignant phenotypes.…”

CDK5 Functions as a Tumor Promoter in Human Lung Cancer

“…These results indicated that CDK5 may function as a tumor activator in lung cancer. CDK5 has been reported up-regulated and to act as a tumor activator in many human cancers, including colorectal cancer 43 , breast cancer 44 , pancreatic cancer 45 . These results showed that CDK5 can be a promising anticancer target.…”

Deciphering the roles of FOXO1 in human neoplasms

“…Tumor‐initiating cells (TIC) account for chemoresistance, tumor recurrence and metastasis and therefore represent a major problem in tumor therapy. Cyclin‐dependent kinase (Cdk5) inhibition induces apoptosis of tumors by stabilizing the transcription factor FOXO1, which is correlated with increased levels of the proapoptosis protein, Bim . Exogenous IGF‐1R promotes the expression of FOXO1 and insulin‐like growth factor binding protein‐1 (IGFBP‐1), evidenced by suppression of breast cancer, whereas IGF‐1R knockdown decreases FOXO1 protein levels and promotes the proliferation of MCF‐7 cells .…”

“…Cyclin-dependent kinase (Cdk5) inhibition induces apoptosis of tumors by stabilizing the transcription factor FOXO1, which is correlated with increased levels of the proapoptosis protein, Bim. 81 Exogenous IGF-1R promotes the expression of FOXO1 and insulin-like growth factor binding protein-1 (IGFBP-1), evidenced by suppression of breast cancer, whereas IGF-1R knockdown decreases FOXO1 protein levels and promotes the proliferation of MCF-7 cells. 82 Moreover, some other studies have demonstrated that FOXO1 can exert antitumor actions in breast cancer, while a detailed description is beyond the scope of this article.…”