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Abstract
Photodynamic therapy (PDT) has been developed as an anticancer treatment, which is based on the tumor-specific accumulation of a photosensitizer that induces cell death after irradiation of light with a specific wavelength. Depending on the subcellular localization of the photosensitizer, PDT could trigger various signal transduction cascades and induce cell death such as apoptosis, autophagy, and necrosis. In this study, we report that both AMP-activated protein kinase (AMPK) and mitogen-activated protein kinase (MAPK) signaling cascades are activated following 5-aminolevulinic acid (ALA)-mediated PDT in both PC12 and CL1-0 cells. Although the activities of caspase-9 and -3 are elevated, the caspase inhibitor zVAD-fmk did not protect cells against ALA-PDT-induced cell death. Instead, autophagic cell death was found in PC12 and CL1-0 cells treated with ALA-PDT. Most importantly, we report here for the first time that it is the activation of AMPK, but not MAPKs that plays a crucial role in mediating autophagic cell death induced by ALA-PDT. This novel observation indicates that the AMPK pathway play an important role in ALA-PDT-induced autophagy.
Highlights
Photodynamic therapy (PDT) has been developed as a modality for cancer treatment which combines the use of low energy light with the photosensitizer [1]
The mitochondrial ATP content decreased 24% 30 minutes after aminolevulinic acid (ALA)-PDT, and further diminished by 77% 6 hours after PDT (Fig. 1D). These results indicate that ALAPDT-induced cell death is related to mitochondrial photodamage
In agreement with previous findings, we found that extracellular signal regulated kinase (ERK), Jun N-terminal kinase (JNK), and p38 were activated in response to ALA-PDT treatment, while the total level of these protein kinases remained constant (Fig. 6A)
Summary
Photodynamic therapy (PDT) has been developed as a modality for cancer treatment which combines the use of low energy light with the photosensitizer [1]. The rapid tumor ablation by PDT involves direct cell killings as well as damage to the exposed microvasculature [2]. Singlet oxygen as well as other reactive oxygen species are the major cytotoxic agents responsible for the PDT-induced cellular damages [3]. Cellular and molecular mechanisms involved in PDT-mediated oxidative stress are becoming clear [4,5]. The signaling pathways involved in the PDT-mediated cell death are not completely understood. Exogenous ALA administration leads to the accumulation of PpIX in the mitochondria, which causes direct mitochondrial damage and subsequent cell death after light irradiation [6].
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