Phospholipase D1 inhibition linked to upregulation of ICAT blocks colorectal cancer growth hyperactivated by Wnt/{beta}-catenin and PI3K/Akt Signaling

Purpose: Dysregulated expression of PLD1 has emerged as a hallmark feature of colorectal cancer (CRC), which remains a major cause of mortality worldwide. Aberrant activation of Wnt/β-catenin signaling is a critical event in the development of CRC. Here, we investigated molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways via ICAT, a negative regulator of Wnt/β-catenin signaling. We also explored the effect of PLD1 inhibition on growth of CRC hyperactivated by Wnt/β-catenin and PI3K/Akt signaling. Experimental design: Expression of ICAT via targeting of PLD1 was assessed in vivo in ApcMin/+ mice, an AOM/DSS model, and in vitro using various CRC cells. The relationship between ICAT/PLD1 expression and prognostic survival value of 153 CRC patients was examined. The therapeutic efficacy of PLD1 inhibitor was determined using a patient-derived xenograft model carrying APC and PI3K mutations. Results: PLD1 promoted the Wnt/β-catenin signaling pathway by selectively down-regulating ICAT via the PI3K/Akt-TopBP1-E2F1 signaling pathways. Low PLD1 expression and high ICAT expression were significantly associated with increased survival in CRC patients and vice versa. Furthermore, PLD1 inhibition suppressed growth of CRC activated by the Wnt/β-catenin and PI3K signaling pathways. Conclusion: These results suggest that PLD1 linked to ICAT mediates molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways and thus could be proposed as a novel CRC prognostic biomarker. These results may assist in the clinical development of a PLD1 inhibitor for treatment of CRC patients carrying APC and PI3KCA mutations.

http://ift.tt/2jS46xv