Involvement of both endoplasmic reticulum and mitochondria in photokilling of nasopharyngeal carcinoma cells by the photosensitizer Zn-BC-AM.
Photodynamic therapy (PDT) is recently developed as an effective treatment for malignant disease. In PDT, the photosensitizer eradicates tumour by induction of apoptosis. In this study, we investigated the mechanistic actions of a recently developed second generation photosensitizer, Zn-BC-AM, on nasopharyngeal carcinoma (NPC) cells. Zn-BC-AM was found to localize in the mitochondria, endoplasmic reticulum (ER), and golgi body. Photoactivation of Zn-BC-AM loaded NPC cells resulted in a rapid collapse of mitochondrial membrane potential (Deltapsim) (15 min), followed by the release of cytochrome c (1 h), and activation of caspases-9 and -3 (4 h). Expression of ER chaperones Bip/Grp78 and Grp94, and ER resident lectin-like chaperone calnexin (CNX) was also enhanced in PDT-stressed NPC cells. Caspase-12, an important caspase involved in ER stress-induced apoptosis, was also activated. Inhibition of Ca2+ uptake into mitochondria by ruthenium red (RR) or loading the cells with EGTA-AM, an agent that buffers intracellular Ca2+ released from ER, resulted in a significant reduction of Zn-BC-AM PDT-induced cell death. These observations suggest that both ER and mitochondria are the subcellular targets of Zn-BC-AM. Effective activation of ER- and mitochondria-mediated apoptotic pathways is responsible for Zn-BC-AM PDT-induced NPC cell death.
Mak
Nai-Ki
NK
Department of Biology, Hong Kong Baptist University, Hong Kong, China. nkmak@hkbu.edu.hk
Li
Kai-Man
KM
Leung
Wing-Nang
WN
Wong
Ricky Ngok-Shun
RN
Huang
Dolly P
DP
Lung
Maria Li
ML
Lau
Yan-Kin
YK
Chang
Chi K
CK
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008665:Metalloporphyrins / Q000138:chemical synthesis / Q000494:pharmacology*; D008928:Mitochondria / Q000502:physiology*; D009303:Nasopharyngeal Neoplasms / Q000473:pathology*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D013347:Subcellular Fractions; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D008665:Metalloporphyrins; D017319:Photosensitizing Agents; C497948:Zn-BC-AM; D020169:Caspases; D002118:Calcium