Figure 7
A hypothetical schematic representation of the effects of the combination of ACR and LY294002 on growth inhibition in HCC cells. When ACR binds to and activates RXRα, it forms homo- and/or heterodimers with other nuclear receptors (NRs), including RARs. This results in the activation of the transcriptional activity of the responsive element, thus controlling the expression of the target genes, such as RARβ, p21CIP1, and cyclin D1, which induce apoptosis and inhibit the growth of HCC cells (A). In HCC cells, the MAPK/ERK and PI3K/Akt pathways, both of which are located downstream of Ras, are highly activated and phosphorylate the RXRα protein. The accumulation of phosphorylated RXRα protein, which impairs dimer formation and the subsequent transactivation functions of this receptor, cause a deviation from normal cell proliferation and differentiation, thereby playing a critical role in liver carcinogenesis (B). ACR and LY294002 inhibit RXRα phosphorylation by inhibiting ERK and Akt phosphorylation, resulting in restoration of receptor function and activation of the transcriptional activity of the responsive element (C). For additional details, see the Discussion section.