Retinoid-related molecules induce cytochrome c release and apoptosis through activation of c-jun NH2-terminal kinase/p38 mitogen-activated protein kinases

Retinoid-related molecules have been described that induce apoptosis in a v ariety of cancer cell lines. Of particular interest is the apoptotic activi ty of the all-trans-retinoic acid receptor gamma -selective molecules MX287 0-1 and MX3350-1. These compounds have been shown to be effective in vivo a gainst lung cancer and could therefore serve as important leads for novel a nticancer drugs. We analyzed the death signaling pathways activated by thes e molecules. We observed that apoptotic retinoid-related molecules (RRMs) c ause the release of cytochrome c from the mitochondria and subsequent activ ation of caspases 9 and 3. This was preceded by a strong and sustained acti vation of c-Jun NH2-terminal kinase as well as p38 kinase, which was indepe ndent or caspase activity. Inhibition of p38 kinase activity by the specifi c inhibitor SB203580 did not affect the induction of apoptosis by MX2870-1. However, interference with the activation of c-Jun NH2-terminal kinase and p38 stress kinases by PD169316 completely blocked all signs of apoptosis, including caspase activity, DNA fragmentation, and phosphatidylserine exter nalization. PD169316 also prevented the cleavage of Bid and the release of cytochrome c induced by this class of RRMs. Furthermore, processing and act ivation of different caspases by MX2870-1 was completely inhibited by incre asing concentrations of PD169316. Thus, the investigated RRMs induce a deat h pathway, which is independent of Fas ligand, that is also activated by UV radiation and other agents. Our findings open the possibility for the futu re use of this class of RRMs in combination therapies with other anticancer drugs.