il\VOLVEMENT OF RETII\OIC ACID II{ - MSpace at the University of ...

IV.e.2.Receptor-independent pathway: The receptor independent pathway of retinoic
acid apoptosis regulation is mediated by its direct effect on the mitochondria. The early
studies have shown that treatment with retinoic acid will cause cell fusion, hemolysis in
hen erythrocytes and will result in the mitochondrial swelling of rat hepatocytes (Goodall
et al. 1980). ATRA treatment was also shown to cause changes in mitochondrial
permeability transition (MPT) in isolated heart mitochondria and in HeLa cells (Notario
et al. 2003). Retinoic acid -induced
changes in MPT are attributed to the inhibition of
adenine nucleotide translocase in the mitochondrial membrane (Notario et al. 2003).
Since changes in mitochondrial structure and changes in the MPT play an important role
in the receptor independent pathway of apoptosis. This indicates that retinoic acid can
cause the apoptosis independently without the activation of its retinoic acid receptors.
Recent data indicates that retinoic acid can mediate its apoptotic effect in promyelocytic
leukemia cells without the activation of RAR or RXR receptors. In this model, retinoic
acid-induced anti-apoptotic effects \trere achieved through the activation of NF-kB.
The initiation of apoptosis is caused by the retinoic acid-induced mitochondrial
damage, the release of caspases and the activation of TRAIL pathway by DR4 and./or
DR5 which will ultimately lead to apoptosis (Altucci et al. 2001). The effects of retinoic
acid on the expression and the activation of caspases was confirmed by the study
perfomed by Gianni et al. (2000). The data from this study documented that
administration of retinoic acid and its isomer 9-cis retinoic acid was able to cause
upregulation of mRNA coding for pro-caspases I, 7 , I and 9, essentially leading to the
upregulation of pro-caspase 1 and 7 proteins. The administration of retinoic acid and its
isomer 9-cis retinoic acid also caused the activation of pro-caspases 6,7, and 8,
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