Phospholipase D1 Inhibition Linked to Upregulation of ICAT Blocks Colorectal Cancer Growth Hyperactivated by Wnt/β-Catenin and PI3K/Akt Signaling

• Published in: Clinical cancer research 2017-12, Vol.23 (23), p.7340-7350
• Main Authors: Kang, Dong Woo, Lee, Bo Hui, Suh, Young-Ah, Choi, Yong-Seok, Jang, Se Jin, Kim, Yong Man, Choi, Kang-Yell, Min, Do Sik
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Aberration; Adenomatous polyposis coli; AKT protein; Animals; beta Catenin - genetics; beta Catenin - metabolism; Biomarkers; Cancer; Cell Line, Tumor; Cells, Cultured; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Crosstalk; Experimental design; Gene Expression Regulation, Neoplastic; Humans; Inhibition; Inhibitors; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Lymphocytes T; Mice, Knockout; Mutation; Patients; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phospholipase; Phospholipase D - genetics; Phospholipase D - metabolism; Phospholipase D1; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Signal transduction; Signal Transduction - genetics; Signaling; Survival; Survival Analysis; Survival value; Transcription factors; Transplantation, Heterologous; Up-Regulation; Wnt protein; Wnt Signaling Pathway - genetics; Xenografts; β-Catenin
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-0749

Dysregulated expression of PLD1 has emerged as a hallmark feature of colorectal cancer, which remains a major cause of mortality worldwide. Aberrant activation of Wnt/β-catenin signaling is a critical event in the development of colorectal cancer. Here, we investigated molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways via inhibitor of β-catenin and T-cell factor (ICAT), a negative regulator of Wnt/β-catenin signaling. We also explored the effect of PLD1 inhibition on growth of colorectal cancer hyperactivated by Wnt/β-catenin and PI3K/Akt signaling. Expression of ICAT via targeting of PLD1 was assessed in mice, an AOM/DSS model, and using various colorectal cancer cells. The relationship between ICAT/PLD1 expression and prognostic survival value of 153 colorectal cancer patients was examined. The therapeutic efficacy of PLD1 inhibitor was determined using a patient-derived xenograft model carrying and mutations. PLD1 promoted the Wnt/β-catenin signaling pathway by selectively downregulating ICAT via the PI3K/Akt-TopBP1-E2F1 signaling pathways. Low PLD1 expression and high ICAT expression were significantly associated with increased survival in colorectal cancer patients and vice versa. Furthermore, PLD1 inhibition suppressed growth of colorectal cancer activated by the Wnt/β-catenin and PI3K signaling pathways. 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 colorectal cancer prognostic biomarker. These results may assist in the clinical development of a PLD1 inhibitor for treatment of colorectal cancer patients carrying and mutations. PLD1, a nodal modifier, acts as a potential therapeutic target for the treatment of colorectal cancer hyperactivated by the Wnt/β-catenin and PI3K/Akt signaling pathways. .