Control of tumor suppressor protein PTEN by dimethlysulfoxide in HL-60 cells

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3156 Background: Dimethylsulfoxide (DMSO) has been used in the treatment of several types of cancer for several decades. However, the mechanism(s) responsible for its anti-tumoral action remains unknown. A novel tumor suppressor gene, PTEN/MMAC, on chromosome 10q23 encodes a phosphatidylinositol-3'-phosphatase (PTEN) that dephosphorylates the D3 position of phosphatidylinositol-3,4,5-triphosphate (PIP3), the second messenger downstream from phosphoinositide 3-kinase (PI 3-kinase) and protein kinase B (PKB)/Akt. PKB/Akt is a Ser/Thr protein kinase implicated in mediating biological responses, including the inhibition of apoptosis and the stimulation of cell growth. The present study was designed to evaluate whether DMSO controls PTEN expression in malignant cell lines. Methods: HL-60 cells were treated with DMSO, and PTEN expression determined by western- and northern-blot analysis. NF-κB activation was measured by electrophoretic mobility shift assay. To investigate the prevention of DMSO-induced PTEN upregulation in HL-60 cells, we blocked NF-κB activity with a p65 antisense oligonucleotide and pyrrolidine dithiocarbamate (PDTC). Results: DMSO strongly induced PTEN expression through NF-κB activation in HL-60 cells. Treatment of HL-60 cells with DMSO caused significant NF-κB activation and induced an increase in PTEN expression in a time- and dose-dependent manner. Interestingly, blocking NF-κB activity prevented the DMSO-induced upregulation of PTEN, indicating that the upregulation of PTEN expression by DMSO is NF-κB-dependent. Conclusion: These results suggest that DMSO is an important stimulator of the tumor suppressor protein PTEN in leukemia cells. These studies form the basis for further investigations to improve the anti-tumor effects of DMSO against such cancers as leukemia and various kinds of solid tumors. No significant financial relationships to disclose.

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