NTP finds arsenic exposure leads to a mutated KRAS allele
National Toxicology Program (NTP) researchers showed that arsenic-induced transformation of a human prostate cell line is driven by a mutant form, called an allele, of KRAS acting as an oncogene that increases cell proliferation. Sequencing of KRAS showed a mutant-specific allelic imbalance frequently seen in primary clinical tumors. These findings revealed molecular mechanisms underlying arsenic-mediated cancer formation.
Arsenic is a well-known environmental carcinogen found in the soil, water, air, and food. Long-term exposure to arsenic has been associated with many cancers, including prostate cancer. NTP researchers previously developed a malignant invasive prostate cancer cell line (CAsE-PE) by long-term, low-level arsenic exposure of a non-tumorigenic human prostate epithelial cell line (RWPE-1). In this study, they performed RNA-Seq and targeted sequencing analysis of both cell lines to identify changes of genes and pathways that may contribute to arsenic-induced carcinogenesis.
Thousands of genes were differentially expressed in CAsE-PE cells compared with parental RWPE-1 cells, with many involved in cell growth and cancer development. CAsE-PE cells substantially overexpressed a mutated and oncogenic KRAS variant commonly seen in tumor cells, which suggested arsenic exposure could lead to accumulation of KRAS mutations, driving transformation of normal cells to cancer. How arsenic causes KRAS overexpression is currently under investigation. (QX)
Citation: Merrick BA, Phadke DP, Bostrom MA, Shah RR, Wright GM, Wang X, Gordon O, Pelch KE, Auerbach SS, Paules RS, DeVito MJ, Waalkes MP, Tokar EJ. 2019. Arsenite malignantly transforms human prostate epithelial cells in vitro by gene amplification of mutated KRAS. PLoS One 14(4):e0215504.