Abstract
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.
Highlights
Cell cycle is a tightly regulated and integrated set of events, which ensures the cell to proliferate and grow by passing through the G1, S, G2 and M phases [1]
8 tumors were characterized with a unit fold change including head and neck squamous cell carcinoma (HNSCC), which ranked among the highest (p = 10–31, fold change = 1.09, Figure 1A and 1B)
Our findings revealed that Head and Neck cancer ranks amongst the top four cancers with deregulated cell cycle processes
Summary
Cell cycle is a tightly regulated and integrated set of events, which ensures the cell to proliferate and grow by passing through the G1, S, G2 and M phases [1]. The core purpose of this regulated event is to make sure that DNA is duplicated during the S phase and distributed to the daughter cells [2]. CDK activity entails binding of regulatory subunits, cyclins, that are synthesized and degraded at specific times during cell cycle progression, regulating kinase activity in a timely manner [4]. This progression has to go through several ‘cell cycle checkpoints’ that sense possible defects during DNA synthesis and chromosome segregation [4]. CDKs govern the initiation, progression, and completion of cell cycle events, and are a major target for deregulation in cancer [5]. Over the last two decades, numerous CDK inhibitors have been developed as cancer therapeutics [6] and various clinical trials in several tumor types have been carried out, reinforcing CDKs/cyclins as potential targets for anticancer drug development [7, 8]
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