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Silencing of human ferrochelatase causes abundant protoporphyrin‐IX accumulation in colon cancer

Hemes and heme proteins are vital components of essentially every cell of virtually every eukaryote organism. Previously, we demonstrated accumulation of the heme precursor protoporphyrin‐IX (PplX) in gastrointestinal tumor tissues. To elucidate the mechanisms of PplX accumulation by quantitative reverse transcriptase‐polymerase chain reaction (RT‐PCR), we studied expression of the relevant enzymes of the heme synthetic pathway. Here, we describe a significant down‐regulation of ferrochelatase (FECH) mRNA expression in gastric, colonic, and rectal carcinomas. Accordingly, in an in vitro model of several carcinoma cell lines, ferrochelatase down‐regulation and loss of enzymatic activity corresponded with an enhanced PpIX‐dependent fluorescence. Direct detection of PpIX in minute amounts was achieved by a specifically developed pulsed solid‐state laser dual delay fluorimetry setup. Silencing of FECH using small interfering RNA (siRNA) technology led to a maximum 50‐fold increased PplX accumulation, imageable by a specifically adapted two‐photon microscopy unit. Our results show that in malignant tissue a transcriptional down‐regulation of FECH occurs, which causes endogenous PpIX accumulation. Furthermore, accumulation of intracellular PplX because of FECH siRNA silencing provides a small‐molecule‐based approach to molecular imaging and molecular therap.—Kemmner, W., Wan, K., Rüttinger, S., Ebert, B., Macdonald, R., Klamm, U., Moesta, K. T. Silencing of human ferrochelatase causes abundant protoporphyrin‐IX accumulation in colon cancer. FASEB J. 22, 500–509 (2008)