Journal
GASTROENTEROLOGY
Volume 135, Issue 4, Pages 1322-1332Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2008.07.012
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Funding
- National Cancer Institutes of Health
- National Cancer Institute
- Center for Cancer Research
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Background & Aims: Resistance to apoptosis is essential for cancer growth. We previously reported that hepatic coexpression of c-Myc and E2F1, 2 key regulators of proliferation and apoptosis, enhanced hepatocellular carcinoma (HCC) development in transgenic mice. Here, we investigated the molecular mechanisms underlying oncogenic cooperation between c-Myc and E2F1 in relationship to human liver cancer. Methods: Activation of pro- and antiapoptoric cascades was assessed by immunoblotting in experimental HCC models and in human HCC. Effect of antisense oligodeoxy nucleotides against c-Myc and E2F1 was studied in human HCC cell fines. Suppression of catalytic subunit p110 alpha of phosphatidylinositol 3-kinase (PIK3CA)/Akt, mammalian target of rapamycin (mTOR), and cyclooxygenase (COX)-2 pathways was achieved by pharmacologic inhibitors and small interfering RNA in human and mouse HCC cell lines. Results: Coexpression with E2F1 did not increase proliferation triggered by c-Myc overexpression but conferred a strong resistance to c-Myc-initiated apoptosis via concomitant induction of PIK3CA/Akt/mTOR and c-Myb/COX-2 survival pathways. COX-2 was not induced in c-Myc and rarely in E2F1 tumors. In human HCC, PIK3CA/Akt/mTOR and c-Myb/COX-2 pathways were similarly activated, with levels of PIK3CA/Akt, mTOR, and c-Myb being inversely associated with patients' survival length. Silencing c-Myc and E2F1 reduced PIK3CA/Akt and mTOR and completely abolished c-Myb and COX-2 expression in human HCC cell fines. Finally, simultaneous inhibition of PIK3CA/Akt/mTOR and COX-2 activity in in vitro models caused massive apoptosis of neoplastic hepatocytes. Conclusions: E2F1 may function as a critical antiapoptotic factor both in human and in rodent liver cancer through its ability to counteract c-Myc-driven apoptosis via activation of PIK3CA/Akt/mTOR and c-Myb/COX-2 pathways.
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