Abstract
Abstract We have recently identified Bim, a pro-apoptotic factor regulated by ERK signaling pathway, is an important mediator of sorafenib-induced apoptosis in HCC cells.. In this study we further explored other possible mediators of sorafenib activity in HCC cells that is independent of mitogen-activated protein kinase-extracellular signal-regulated kinase (MEK)/ERK signaling. Huh7 cells were treated with sorafenib or the MEK inhibitor CI-1040, alone or in combination, for 24 hours. The gene expression profiles were analyzed by Affymetrix oligonucleotide microarray analysis using HG_U133A chip, and the candidate genes were selected if (1) they had > 1.2 fold or < 0.8 fold change than control after treatment with sorafenib 10 M and (2) they had been reported to be involved in important carcinogenesis-related cellular signaling pathways, such as apoptosis regulation, cell proliferation/survival, cell cycle control, and angiogenesis. The gene expression was considered MEK/ERK-dependent if the direction of changes was similar after treatment with sorafenib 10 M or CI-1040 1 M; otherwise it was considered MEK/ERK-independent. Thirty candidate genes of interest were identified and the expression patterns were validated by real-time PCR (see table). The 14 genes whose expressions were considered ERK-independent involved apoptosis regulation (GADD45b, BAX, JUN), cell proliferation (PCNA, RPS6KA3, SMAD7, BMP2, DUSP1, DUSP8, IL1RAP, RHEB), cell cycle control (CCNE1, CDC25A), and angiogenesis (VEGF). Validation of the biological significance of these markers is ongoing. The preliminary data revealed that induction of GADD45b and JUN gene expression after sorafenib treatment was correlated with intrinsic or acquired resistance of HCC cells to sorafenib. Our data indicated that MEK/ERK-independent signaling pathways may also contribute to sorafenib-induced apoptosis and growth regulation in HCC cells. The signaling molecules identified in this study can serve as novel therapeutic targets for HCC. (Supported by grants NSC97-3112-B-002-012, NSC98-3112-B-002-007, NSC98-3112-B-002-037) Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A241.
Published Version
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