Cancer Therapeutics Insights TheCannabinoidWIN 55,212-2Decreases Specificity Protein Transcription Factors and the Oncogenic Cap Protein eIF4E in Colon Cancer Cells

2,3-Dihydro-5-methyl-3-([morpholinyl]methyl)pyrollo(1,2,3-de)-1,4-benzoxazinyl]-[1-naphthaleny]methanone [WIN 55,212-2, (WIN)] is a synthetic cannabinoid that inhibits RKO, HT-29, and SW480 cell growth, induced apoptosis, and downregulated expression of survivin, cyclin D1, EGF receptor (EGFR), VEGF, and its receptor (VEGFR1). WIN also decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4, and this is consistent with the observed downregulation of the aforementioned Sp-regulated genes. In addition, we also observed by RNA interference (RNAi) that the oncogenic cap protein eIF4E was an Sp-regulated gene also downregulated byWIN in colon cancer cells. WIN-mediated repression of Sp proteins was not affected by cannabinoid receptor antagonists or by knockdown of the receptor but was attenuated by the phosphatase inhibitor sodium orthovanadate or by knockdown of protein phosphatase 2A (PP2A). WIN-mediated repression of Sp1, Sp3, andSp4wasdue toPP2A-dependent downregulation ofmicroRNA-27a (miR-27a) and induction of miR-27a–regulated ZBTB10, which has previously been characterized as an "Sp repressor." The results show that the anticancer activity ofWIN is due, in part, to PP2A-dependent disruption of miR-27a:ZBTB10 and ZBTB10-mediated repression of Sp transcription factors and Sp-regulated genes, including eIF4E. Mol Cancer Ther; 12(11); 2483–93. 2013 AACR.