Journal
EMBO JOURNAL
Volume 37, Issue 13, Pages -Publisher
WILEY
DOI: 10.15252/embj.201798354
Keywords
Golgi apparatus; Golgi-targeting agents; photodynamic therapy; redaporfin; retrograde transport
Categories
Funding
- Portuguese Science Foundation [SFRH/BPD/93562/2013]
- Chinese Scholarship Council
- Ligue contre le Cancer
- Ligue contre le Cancer (equipe labelisee)
- Agence National de la Recherche (ANR)-Projets blancs
- ANR
- Association pour la recherche sur le cancer (ARC)
- Canceropole Ile-de-France
- Institut National du Cancer (INCa)
- Institut Universitaire de France
- Fondation pour la Recherche Medicale [FDM20140630126, FDM 40739]
- European Commission (ArtForce)
- European Research Council (ERC)
- LeDucq Foundation
- LabEx Immuno-Oncology
- RHU Torino Lumiere, the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- Paris Alliance of Cancer Research Institutes (PACRI)
- Centre National de la Recherche Scientifique (CNRS)
- Institut Curie
- LabEx CelTisPhyBio (IDEX PSL) [ANR-10-LBX-0038, ANR-10-IDEX-0001-02]
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Preclinical evidence depicts the capacity of redaporfin (Redp) to act as potent photosensitizer, causing direct antineoplastic effects as well as indirect immune-dependent destruction of malignant lesions. Here, we investigated the mechanisms through which photodynamic therapy (PDT) with redaporfin kills cancer cells. Subcellular localization and fractionation studies based on the physicochemical properties of redaporfin revealed its selective tropism for the endoplasmic reticulum (ER) and the Golgi apparatus (GA). When activated, redaporfin caused rapid reactive oxygen species-dependent perturbation of ER/GA compartments, coupled to ER stress and an inhibition of the GA-dependent secretory pathway. This led to a general inhibition of protein secretion by PDT-treated cancer cells. The ER/GA play a role upstream of mitochondria in the lethal signaling pathway triggered by redaporfin-based PDT. Pharmacological perturbation of GA function or homeostasis reduces mitochondrial permeabilization. In contrast, removal of the pro-apoptotic multidomain proteins BAX and BAK or pretreatment with protease inhibitors reduced cell killing, yet left the GA perturbation unaffected. Altogether, these results point to the capacity of redaporfin to kill tumor cells via destroying ER/GA function.
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