Gambogic acid, a novel ligand for transferrin receptor, potentiates TNF-induced apoptosis through modulation of the nuclear factor-κB signaling pathway (Publication with Expression of Concern)

Gambogic acid (GA), a xanthone derived from the resin of the Garcinia hanburyi, has been recently demonstrated to bind transferrin receptor and exhibit potential anticancer effects through a signaling mechanism that is not fully understood. Because of the critical role of NF-kappa B signaling pathway, we investigated the effects of GA on NF-kappa B-mediated cellular responses and NF-kappa B-regulated gene products in human leukemia cancer cells. Treatment of cells with GA enhanced apoptosis induced by tumor necrosis factor (TNF) and chemotherapeutic agents, inhibited the expression of gene products involved in antiapoptosis (lAP1 and IAP2, Bcl-2, Bcl-X-L, and TRAF1), proliferation (cyclin 1311 and c-Myc), invasion (COX-2 and MMP-9), and angiogenesis (VEGF), all of which are known to be regulated by NF-kappa B. GA suppressed NF-kappa B activation induced by various inflammatory agents and carcinogens and this, accompanied by the inhibition of TAKI/TAB1-mediated IKK activation, inhibited IKB alpha phosphorylation and degradation, suppressed p65 phosphorylation and nuclear translocation, and finally abrogated NF-kappa B-dependent reporter gene expression. The NF-kappa B activation induced by TNFR1, TRADD, TRAF2, NIK, TAK1/TAB1, and lKK beta was also inhibited. The effect of GA mediated through transferrin receptor as down-regulation of the receptor by RNA interference reversed its effects on NF-kappa B and apoptosis. Overall our results demonstrate that GA inhibits NF-kappa B signaling pathway and potentiates apoptosis through its interaction with the transferrin receptor.