Photodynamic therapy induces autophagy-mediated cell death in human colorectal cancer cells via activation of the ROS/JNK signaling pathway

Abstract

Evidence has shown that m-THPC and verteporfin (VP) are promising sensitizers in photodynamic therapy (PDT). In addition, autophagy can act as a tumor suppressor or a tumor promoter depending on the photosensitizer (PS) and the cancer cell type. However, the role of autophagy in m-THPC- and VP-mediated PDT in in vitro and in vivo models of human colorectal cancer (CRC) has not been reported. In this study, m-THPC-PDT or VP-PDT exhibited significant phototoxicity, inhibited proliferation, and induced the generation of large amounts of reactive oxygen species (ROS) in CRC cells. From immunoblotting, fluorescence image analysis, and transmission electron microscopy, we found extensive autophagic activation induced by ROS in cells. In addition, m-THPC-PDT or VP-PDT treatment significantly induced apoptosis in CRC cells. Interestingly, the inhibition of m-THPC-PDT-induced autophagy by knockdown of ATG5 or ATG7 substantially inhibited the apoptosis of CRC cells. Moreover, m-THPC-PDT treatment inhibited tumorigenesis of subcutaneous HCT116 xenografts. Meanwhile, antioxidant treatment markedly inhibited autophagy and apoptosis induced by PDT in CRC cells by inactivating JNK signaling. In conclusion, inhibition of autophagy can remarkably alleviate PDT-mediated anticancer efficiency in CRC cells via inactivation of the ROS/JNK signaling pathway. Our study provides evidence for the therapeutic application of m-THPC and VP in CRC.

Photodynamic Therapy—Current Limitations and Novel Approaches

“…A recent study with HCT116 and SW480 colorectal carcinoma cell lines proposed that PDT with meta -tetrahydroxyphenylchlorin ( m -THPC) and verteporfin (VP) activated the ROS/JNK signaling pathway in cells. In addition, PDT induced autophagy mediated cell death through activation of the ROS/JNK signaling pathway ( Song et al, 2020 ).…”

Nanoparticle-Mediated Delivery Systems in Photodynamic Therapy of Colorectal Cancer

“…Autophagy is thought to be a regulated pathway that is strongly associated with lysosomal degradation of cytoplasmic organelles or cytosolic components [30,34]. This pathway is characterized by double membrane vesicles known as autophagosomes which transport degraded cytoplasmic constituents to the lysosome [11].…”

“…This pathway is characterized by double membrane vesicles known as autophagosomes which transport degraded cytoplasmic constituents to the lysosome [11]. Autophagy is critically involved in cellular homeostasis and cell survival, along with the continuous turnover of cellular components through the degradation of cytoplasmic components, and the recycling of the redundant products [30,34]. Although autophagy has been considered as a cell survival mechanism, evidence relating to the autophagy-induced cell death in PDT application continues to accrue [34,35].…”

“…Autophagy is critically involved in cellular homeostasis and cell survival, along with the continuous turnover of cellular components through the degradation of cytoplasmic components, and the recycling of the redundant products [30,34]. Although autophagy has been considered as a cell survival mechanism, evidence relating to the autophagy-induced cell death in PDT application continues to accrue [34,35]. Moreover, inhibition of autophagy could serve as a potential avenue for PDT-mediated anticancer therapy [34,35].…”

“…Although autophagy has been considered as a cell survival mechanism, evidence relating to the autophagy-induced cell death in PDT application continues to accrue [34,35]. Moreover, inhibition of autophagy could serve as a potential avenue for PDT-mediated anticancer therapy [34,35]. Song et al [34] reported that m-tetra (hydroxyphenyl)chlorin (m-THPC)-PDT treatment induced apoptosis and autophagy in CRC cells through the upregulation of ROS, activation of the JNK pathway and inhibition of the mTOR/p70S6K pathway [34].…”