Endoplasmic reticulum-targeting photosensitizer Hypericin confers chemo-sensitization towards oxaliplatin through inducing pro-death autophagy |
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| Institution: | 1. State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, PO Box 268, 130 Meilong Road, Shanghai 200237, PR China;2. Department of General Surgery, Xinhua Hospital, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai 200092, PR China;1. Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, SP, Brazil;2. Instituto de Ciências Exatas e da Terra, Universidade Federal de Mato Grosso Av. Universitária, 3500, 78698-000 Pontal do Araguaia, MT, Brazil;1. Department of Dermatology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China;2. Department of Dermatology, Medical University of Vienna, Vienna, Austria;1. Teaching & Research Department, The First People''s Hospital of Urumqi, 1 Jiankang Road, Urumqi, Xinjiang Uygur Autonomous Region, China;2. School of Public Health, Xinjiang Medical University, 393 Xinyi Road, Urumqi, Xinjiang Uygur Autonomous Region, China;1. Department of Biophysics, Faculty of Science, P. J. Safarik University in Kosice, 041 54, Kosice, Slovakia;2. Center for Interdisciplinary Biosciences, Technology and Innovation Park, P.J. Safarik University in Kosice, 041 54, Kosice, Slovakia;1. Department of Biophysics, Faculty of Science, P. J. Safarik University in Kosice, Jesenna 5, 041 54 Kosice, Slovak Republic;2. Laboratory of Laser Microscopy and Spectroscopy, International Laser Centre, Ilkovicova 3, 841 04 Bratislava, Slovak Republic;3. Center for Interdisciplinary Biosciences, Technology and Innovation Park, P. J. Safarik University in Kosice, Jesenna 5, 041 54 Kosice, Slovak Republic |
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| Abstract: | Hypericin is an endoplasmic reticulum (ER)-located photosensitizer, which causes oxidative damage to ER during photodynamic therapy (PDT). Hypericin-mediated PDT (HY-PDT) has been confirmed to enhance chemo-sensitivity of oxaliplatin (L-OHP) in colon cancer cells. The present study reveals that autophagy plays a key role in chemosensitization during HY-PDT. We proved pro-death autophagy was required for sensitization and HY-PDT/L-OHP antitumor synergism. High dosage of HY-PDT induced autophagic cell death; while low dose of HY-PDT predominantly triggered protective autophagy and promoted cell proliferation. Low dose of HY-PDT reduced the cytotoxicity of L-OHP in oxaliplatin-resistant colon cancer cells. Different level of autophagy therefore contributed to the opposite effect of HY-PDT on cell fate and chemo-sensitivity. Furthermore, we revealed the role of CHOP as a regulator connecting pro-survival and pro-death autophagy under ER damage. High dose of HY-PDT induced massive ROS generation and severe ER stress, which then led to induction of CHOP. CHOP thereby activated CHOP/TRIB3/Akt/mTOR cascade and triggered autophagic cell death. Additionally, when apoptotic pathway was blocked, cells treated with high dose of HY-PDT preferentially underwent death through autophagic pathway. On the other hand, suppression of autophagy made cells more vulnerable to apoptosis under low dose of HY-PDT. These results provided new evidences for the clinical application of ER-targeting PDT in modifying chemosensitivity of colorectal cancer therapy. |
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| Keywords: | Endoplasmic reticulum (ER) Photodynamic therapy (PDT) Autophagic cell death Chemo-sensitization |
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