Silencing of human ferrochelatase causes abundant protoporphyrin‐IX accumulation in colon cancer
Abstract
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 (PpIX) in gastrointestinal tumor tissues. To elucidate the mechanisms of PpIX 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 PpIX 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 PpIX because of FECH siRNA silencing provides a small-molecule-based approach to molecular imaging and molecular therapy.
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Genetic silencing of FECH significantly increases ALA-PpIX fluorescence in multiple cell lines and even in an animal study.
“Although genetic silencing of FECH significantly increases ALA-PpIX fluorescence in multiple cell lines [108,109,110,111] and even in an animal study [112], pharmacological inhibition of FECH with enzymatic inhibitors for the enhancement of PpIX has not been well studied.”
From 5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy (2023) · cites this paper as [108]
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- Authors
- Kemmner, W., Wan, K., Rüttinger, S., Ebert, B., Macdonald, R., Klamm, U., & Moesta, K. T.
- Affiliations
- Max Delbrück Center (DE)
- Physikalisch-Technische Bundesanstalt (DE)
- Charité – Universitätsmedizin Berlin (DE)
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2007-09-17
- Volume
- 22
- Issue
- 2
- Pages
- 500-509
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2035997627
- Cited by
- 114
- References
- 27
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 9 · 2021: 11 · 2020: 6 · 2019: 8 · 2018: 8 · 2017: 3 · 2016: 10 · 2015: 14 · 2014: 4 · 2013: 5 · 2012: 8
- FWCI
- 1.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (DFG Mo534/4)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Porphyrin Metabolism and Disorders
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Photodynamic Therapy Research Studies
- Physical Sciences › Materials Science › Materials Chemistry › Porphyrin and Phthalocyanine Chemistry
- Keywords
- ferrochelatase, protoporphyrin IX, colon cancer, heme biosynthesis, two-photon microscopy, molecular imaging, molecular therapy, gastric cancer, rectal cancer
- MeSH terms
- Aminolevulinic Acid, Colonic Neoplasms, Ferrochelatase, Heme, Heme Oxygenase (Decyclizing), Humans, Protoporphyrins, RNA, Messenger, Stomach Neoplasms, Gene Expression Regulation, Enzymologic, RNA, Small Interfering, Cell Line, Tumor
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