title: Endoplasmic reticulum-targeting photosensitizer Hypericin confers chemo-sensitization towards oxaliplatin through inducing pro-death autophagy.
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.
authors.affiliation: 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.
authors.forename: Shengchao
authors.initials: S
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Liyan
authors.initials: L
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Wenpei
authors.initials: W
authors.lastname: Du
authors.affiliation: 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.
authors.forename: Yingxue
authors.initials: Y
authors.lastname: Qi
authors.affiliation: 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.
authors.forename: Cen
authors.initials: C
authors.lastname: Qiu
authors.affiliation: 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. Electronic address: xin.liang@ecust.edu.cn.
authors.forename: Xin
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of General Surgery, Xinhua Hospital, Shanghai Jiaotong University, 1665 Kongjiang Road, Shanghai 200092, PR China. Electronic address: weibindr@aliyun.com.
authors.forename: Weibin
authors.initials: W
authors.lastname: Shi
authors.affiliation: 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. Electronic address: liujian@ecust.edu.cn.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D000873:Anthracenes; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology; D017319:Photosensitizing Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000873:Anthracenes; D009944:Organoplatinum Compounds; D017319:Photosensitizing Agents; D017382:Reactive Oxygen Species; D000077150:Oxaliplatin; D010569:Perylene; C004965:hypericin
keywords: Autophagic cell death; Chemo-sensitization; Endoplasmic reticulum (ER); Photodynamic therapy (PDT)