| First Author | Kang DW | Year | 2017 |
| Journal | Cancer Res | Volume | 77 |
| Issue | 1 | Pages | 142-152 |
| PubMed ID | 27793841 | Mgi Jnum | J:237995 |
| Mgi Id | MGI:5817837 | Doi | 10.1158/0008-5472.CAN-15-3032 |
| Citation | Kang DW, et al. (2017) Phospholipase D1 Acts through Akt/TopBP1 and RB1 to Regulate the E2F1-Dependent Apoptotic Program in Cancer Cells. Cancer Res 77(1):142-152 |
| abstractText | The RB1/E2F1 signaling pathway is frequently deregulated in colorectal cancer and has been suggested to intersect with Wnt/beta-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 beta-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. (c)2016 AACR. |
