Abstract
Purpose: 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.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 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 APC and PI3K mutations.Results: 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.Conclusions: 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 APC and PI3KCA 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. Clin Cancer Res; 23(23); 7340-50. ©2017 AACR.
Highlights
In colorectal cancer, the Wnt/b-catenin and PI3K/Akt signaling pathways are frequently dysregulated due to activating mutations in APC and the p110a subunit of PI3K
Low PLD1 expression and high inhibitor of b-catenin and T-cell factor (ICAT) expression were significantly associated with increased survival in colorectal cancer patients and vice versa
These results suggest that PLD1 linked to ICAT mediates molecular crosstalk between the Wnt/b-catenin and PI3K/Akt pathways and could be proposed as a novel colorectal cancer prognostic biomarker
Summary
The Wnt/b-catenin and PI3K/Akt signaling pathways are frequently dysregulated due to activating mutations in APC and the p110a subunit of PI3K. Wnt/b-catenin oncogenic signaling confers resistance to apoptosis promoted by PI3K or Akt-inhibitory drugs [3, 4]. Integration of these two important signaling pathways enhances cancerous growth in tumors and confers resistance against targeted therapies. The molecular mechanism responsible for crosstalk between the Wnt/ b-catenin and PI3K/Akt pathways in cancer remains elusive. Abnormal activation of the Wnt/b-catenin pathway by mutation of APC is responsible for the initiation and progression of almost all colorectal cancers [5]. PLD or its product PA is known to regulate a variety of homeostatic cellular functions such as cell proliferation, survival, 7340 Clin Cancer Res; 23(23) December 1, 2017
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