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

Changfeng Song,Lin Zhou,Wen Xu,Hongkun Wu,Chang Liu,Qianyi Gong,Xiaotong Wang,Jianwen Liu

doi:10.1038/s41419-020-03136-y

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.

Highlights

Colorectal cancer (CRC) is the third leading cause of cancer death globally, with a high incidence and mortality rate[1]
We aimed to investigate whether m-THPC-photodynamic therapy (PDT) or VP-PDT treatment has an anticancer effect in CRC cells and explore the roles of autophagy in PDT treatment in CRC
These data indicated that m-THPC-PDT or VP-PDT had a strong phototoxic effect on CRC cells

Summary

Introduction

Colorectal cancer (CRC) is the third leading cause of cancer death globally, with a high incidence and mortality rate[1]. Song et al Cell Death and Disease (2020)11:938 components, namely a nontoxic photosensitizer (PS), a light source, and oxygen[10]. During PDT, PSs absorb visible light and convert energy to surrounding molecular oxygen and generate a range of highly reactive oxygen species (ROS), such as singlet oxygen, superoxide anions, and hydroxyl radicals[11,12]. High levels of ROS can rapidly cause significant toxicity, which eventually leads to cell death via apoptosis, autophagy, and/or necrosis[13,14]. Metatetrahydroxyphenylchlorin (m-THPC) and verteporfin (VP) are second-generation photosensitizers that exhibit considerable photocytotoxicity to various tumor cells[16,17]

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