Retinol Inhibits PI3K/Akt Activity but does not affect IRS‐1 and PI3K levels in Retinoic Acid‐Resistant Human Colon Cancer Cells

Abstract

We have shown previously that retinol inhibits the invasion of all‐trans‐retinoic acid (ATRA)‐resistant human colon cancer cell lines through a retinoic acid receptor (RAR)‐independent mechanism by decreasing the activity of MMP‐2 and ‐9. The objective of the current study was to determine the mechanism by which retinol inhibits metastasis. The ATRA‐resistant colon cancer cell lines HCT‐116 and SW620 an were treated for 24 h with 0, 1 or 10 microM retinol. Retinol treatment decreased the activity of phosphoinositide 3‐kinase (PI3K) and Akt in both cell lines. Moreover, transfection with a constitutively active Akt blocked retinol¡¯s inhibitory effect on cell invasion. To determine the effect of retinol on the PI3K/Akt signaling pathway upstream of Akt, we examined the effect of retinol on the protein levels of insulin receptor substrate 1 (IRS‐1) and the PI3K subunits, p85 and p110, as well as the phosphorylation of IRS‐1. Retinol did not alter the protein levels of IRS‐1, p85, and p‐110 or IRS‐1 phosphorylation. In conclusion, retinol inhibits cell invasion by decreasing PI3K and Akt activity; however retinol does not affect PI3K or IRS‐1 protein levels or phosphorylation. Supported by Research Scholar Grant # 03‐233‐01‐CNE from the American Cancer Society.