The p53-Dependent Expression of Frataxin Controls 5-Aminolevulinic Acid-Induced Accumulation of Protoporphyrin IX and Photo-Damage in Cancerous Cells

Mitochondrial frataxin is involved in various functions such as iron homeostasis, iron–sulfur cluster biogenesis, the protection from oxidative stress and apoptosis and acts as a tumor suppressor protein. We now show that the expression of frataxin is stimulated in a p53‐dependent manner and prove that frataxin is a direct p53 target gene by showing that the p53‐responsive element in the promoter of the mouse frataxin gene is bound by p53. The bacterial expression of human frataxin stimulated maturation of human ferrochelatase, which catalyzes the insertion of iron into protoporphyrin at the last step of heme biosynthesis. Overexpression of frataxin in human cancer A431 and HeLa cells lowered 5‐aminolevulinic acid(ALA)‐induced accumulation of protoporphyrin and induced resistance to ALA‐induced photo‐damage, whereas p53 silencing with siRNA in non tumor HEK293T cells down‐regulated the expression of frataxin and increased the accumulation of protoporphyrin. Thus, the decrease of the expression of frataxin unregulated by p53 in tumor cells enhances ALA‐induced photo‐damage, by down‐regulation of mitochondrial functions. The expression of frataxin is dependent on the function of the tumor suppressor protein p53 at the transcriptional level. The knockdown of p53 by siRNA in HEK293T cells caused the decrease of the expression of frataxin, leading to enhancement of the ALA‐induced accumulation of protoporphyrin. In contrast, overexpression of frataxin in human cancerous cells lowered the accumulation of protoporphyrin by up‐regulation of mitochondrial functions and induced resistance to ALA‐induced photo‐damage, suggesting that dysfunction of p53 in tumor cells leads to the increase in the ALA‐induced accumulation of protoporphyrin through the decrease of the expression of frataxin.