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Supplementary Figure Legends from Phospholipase D1 Acts through Akt/TopBP1 and RB1 to Regulate the E2F1-Dependent Apoptotic Program in Cancer Cells

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posted on 2023-03-31, 00:30 authored by Dong Woo Kang, Shin Wha Lee, Won Chan Hwang, Bo Hui Lee, Yong-Seok Choi, Young-Ah Suh, Kang-Yell Choi, Do Sik Min

Legend for supplementary figures.

Funding

National Research Foundation of Korea

Translational Research Center for Protein Function Control

Ministry for Health, Welfare, and Family Affairs

Korean Health Technology R&D Project

History

ARTICLE ABSTRACT

The RB1/E2F1 signaling pathway is frequently deregulated in colorectal cancer and has been suggested to intersect with Wnt/β-catenin and PI3K/Akt pathways, but molecular evidence for this link is lacking. In this study, we demonstrate that phospholipase D1 (PLD1), a transcriptional target of β-catenin/TCF4, orchestrates functional interactions between these pathways during intestinal tumor development. Overexpression of PLD1 in intestinal epithelial cells protected cells from apoptosis induced by PLD1 ablation in the Apcmin/+ mouse model of intestinal tumorigenesis. Mechanistic investigations revealed that genetic and pharmacologic targeting of PLD1 promote the E2F1-dependent apoptotic program via both miR-192/4465–mediated downregulation of RB1 and inhibition of Akt–TopBP1 pathways. Moreover, the miRNA–RB1 axis and Akt pathway also contributed to the PLD1-mediated self-renewal capacity of colon cancer–initiating cells. Finally, PLD1-driven E2F1 target gene expression positively correlated with tumor stage in patients with colorectal cancer. Overall, our findings suggest that PLD1 mediates cross-talk between multiple major signaling pathways to promote the survival and malignancy of colon cancer cells and may therefore represent an ideal signaling node for therapeutic targeting. Cancer Res; 77(1); 142–52. ©2016 AACR.

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    Cancer Research

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    Keywords

    Cancer PreventionAnimal models of preventionCell CycleSignal transduction pathwaysCell Death And SenescenceTranscriptional control of apoptosisDrug MechanismsCellular responses to anticancer drugsDrug ResistanceRegulation of gene expression in drug resistanceGastrointestinal CancersColorectal cancerGene RegulationPosttranscriptional and translational controlOncogenes & Tumor SuppressorsTumor suppressor genesPreclinical ModelsAnimal models of cancer

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