Research Papers:

Upregulation of cell cycle genes in head and neck cancer patients may be antagonized by erufosine's down regulation of cell cycle processes in OSCC cells

Shariq S. Ansari, Ashwini K. Sharma, Michael Zepp, Elizabet Ivanova, Frank Bergmann, Rainer König and Martin R. Berger _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2018; 9:5797-5810. https://doi.org/10.18632/oncotarget.23537

Metrics: PDF 1739 views  |   HTML 2492 views  |   ?  


Shariq S. Ansari1, Ashwini K. Sharma2,3, Michael Zepp1, Elizabet Ivanova4, Frank Bergmann5, Rainer König6,7 and Martin R. Berger1

1Toxicology and Chemotherapy Unit, German Cancer Research Center, Heidelberg, Germany

2Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany

3Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany

4Laboratory for Experimental Chemotherapy, Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Bulgaria

5Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

6Integrated Research and Treatment Center Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany

7Network Modeling, Leibniz Institute for Natural Products Research and Infection Biology, Hans-Knöll-Institute, Jena, Germany

Correspondence to:

Martin R. Berger, email: [email protected]

Keywords: erufosine; head and neck cancer; cyclins and CDKs; G2/M block; OSCC xenograft mouse model

Received: October 27, 2017     Accepted: December 01, 2017     Published: December 20, 2017


The TCGA database was analyzed to identify deregulation of cell cycle genes across 24 cancer types and ensuing effects on patient survival. Pan-cancer analysis showed that head and neck squamous cell carcinoma (HNSCC) ranks amongst the top four cancers showing deregulated cell cycle genes. Also, the median gene expression of all CDKs and cyclins in HNSCC patient samples was higher than that of the global gene expression. This was verified by IHC staining of CCND1 from HNSCC patients. When evaluating the quartiles with highest and lowest expression, increased CCND1/CDK6 levels had negative implication on patient survival. In search for a drug, which may antagonize this tumor profile, the potential of the alkylphosphocholine erufosine was evaluated against cell lines of the HNSCC subtype, oral squamous cell carcinoma (OSCC) using in-vitro and in-vivo assays. Erufosine inhibited growth of OSCC cell lines concentration dependently. Initial microarray findings revealed that cyclins and CDKs were down-regulated concentration dependently upon exposure to erufosine and participated in negative enrichment of cell cycle processes. These findings, indicating a pan-cdk/cyclin inhibition by erufosine, were verified at both, mRNA and protein levels. Erufosine caused a G2/M block and inhibition of colony formation. Significant tumor growth retardation was seen upon treatment with erufosine in a xenograft model. For the decreased cyclin D1 and CDK 4/6 levels found in tumor tissue, these proteins can serve as biomarker for erufosine intervention. The findings demonstrate the potential of erufosine as cell cycle inhibitor in HNSCC treatment, alone or in combination with current therapeutic agents.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 23537