Highly expressed genes in rapidly proliferating tumor cells as new targets for colorectal cancer treatment

Sarah Bazzocco, Higinio Dopeso, Fernando Carton-Garcia, Irati Macaya, Elena Andretta, Fiona Chionh, Paulo Rodrigues, Miriam Garrido, Hafid Alazzouzi, Rocio Nieto, Alex Sanchez, Simo Schwartz, Josipa Bilic, John M. Mariadason, Diego Arango

    Research output: Contribution to journalArticleResearchpeer-review

    9 Citations (Scopus)

    Abstract

    © 2015 American Association for Cancer Research. Purpose: The clinical management of colorectal cancer patients has significantly improved because of the identification of novel therapeutic targets such as EGFR and VEGF. Because rapid tumor proliferation is associated with poor patient prognosis, here we characterized the transcriptional signature of rapidly proliferating colorectal cancer cells in an attempt to identify novel candidate therapeutic targets. Experimental Design: The doubling time of 52 colorectal cancer cell lines was determined and genome-wide expression profiling of a subset of these lines was assessed by microarray analysis. We then investigated the potential of genes highly expressed in cancer cells with faster growth as new therapeutic targets. Results: Faster proliferation rates were associated with microsatellite instability and poorly differentiated histology. The expression of 1,290 genes was significantly correlated with the growth rates of colorectal cancer cells. These included genes involved in cell cycle, RNA processing/splicing, and protein transport. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and protoporphyrinogen oxidase (PPOX) were shown to have higher expression in faster growing cell lines and primary tumors. Pharmacologic or siRNA-based inhibition of GAPDH or PPOX reduced the growth of colon cancer cells in vitro. Moreover, using a mouse xenograft model, we show that treatment with the specific PPOX inhibitor acifluorfen significantly reduced the growth of three of the seven (42.8%) colon cancer lines investigated. Conclusions: We have characterized at the transcriptomic level the differences between colorectal cancer cells that vary in their growth rates, and identified novel candidate chemotherapeutic targets for the treatment of colorectal cancer.
    Original languageEnglish
    Pages (from-to)3695-3704
    JournalClinical Cancer Research
    Volume21
    Issue number16
    DOIs
    Publication statusPublished - 15 Aug 2015

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