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Retinoid-related Molecules Induce Cytochrome c Release and Apoptosis through Activation of c-Jun NH₂-Terminal Kinase/p38 Mitogen-activated Protein Kinases¹

Sidney Kimmel Cancer Center, San Diego, California 92121 [M. A. O., F. J. L-H., Y. B., M. P., F. J. P.], and MAXIA Pharmaceuticals, San Diego, California 92121 [M. P.]

Retinoid-related molecules have been described that induce apoptosis in a variety of cancer cell lines. Of particular interest is the apoptotic activity of the all-trans-retinoic acid receptor -selective molecules MX2870-1 and MX3350-1. These compounds have been shown to be effective in vivo against lung cancer and could therefore serve as important leads for novel anticancer drugs. We analyzed the death signaling pathways activated by these molecules. We observed that apoptotic retinoid-related molecules (RRMs) cause the release of cytochrome c from the mitochondria and subsequent activation of caspases 9 and 3. This was preceded by a strong and sustained activation of c-Jun NH₂-terminal kinase as well as p38 kinase, which was independent of caspase activity. Inhibition of p38 kinase activity by the specific 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 externalization. PD169316 also prevented the cleavage of Bid and the release of cytochrome c induced by this class of RRMs. Furthermore, processing and activation of different caspases by MX2870-1 was completely inhibited by increasing concentrations of PD169316. Thus, the investigated RRMs induce a death pathway, which is independent of Fas ligand, that is also activated by UV radiation and other agents. Our findings open the possibility for the future use of this class of RRMs in combination therapies with other anticancer drugs.

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