Endoplasmic reticulum-targeting photosensitizer Hypericin confers chemo-sensitization towards oxaliplatin through inducing pro-death autophagy

• Published in: The international journal of biochemistry & cell biology 2017-06, Vol.87, p.54-68
• Main Authors: Lin, Shengchao, Yang, Liyan, Shi, Haiyang, Du, Wenpei, Qi, Yingxue, Qiu, Cen, Liang, Xin, Shi, Weibin, Liu, Jianwen
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Autophagic cell death; Autophagy - drug effects; Chemo-sensitization; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Endoplasmic reticulum (ER); Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Stress - drug effects; Female; HCT116 Cells; Humans; Mice; Organoplatinum Compounds - pharmacology; Perylene - analogs & derivatives; Perylene - pharmacology; Photodynamic therapy (PDT); Photosensitizing Agents - pharmacology; Reactive Oxygen Species - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1357-2725; 1878-5875
• DOI: 10.1016/j.biocel.2017.04.001

[Display omitted] •Endoplasmic reticulum-located hypericin induced autophagy under photodynamic therapy.•Pro-death autophagy was required for chemo-sensitization towards L-OHP by HY-PDT.•CHOP was molecular switch connecting ER stress and pro-death autophagy under HY-PDT.•CHOP/TRIB3/AKT/mTOR cascade amplified autophagy and triggered autophagic cell death. 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.