Lin Shengchao, Yang Liyan, Shi Haiyang, Du Wenpei, Qi Yingxue, Qiu Cen, Liang Xin, Shi Weibin, Liu Jianwen
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.
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.
Int J Biochem Cell Biol. 2017 Jun;87:54-68. doi: 10.1016/j.biocel.2017.04.001. Epub 2017 Apr 6.
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.
金丝桃素是一种定位于内质网（ER）的光敏剂，在光动力疗法（PDT）过程中会对内质网造成氧化损伤。金丝桃素介导的光动力疗法（HY-PDT）已被证实可增强结肠癌细胞对奥沙利铂（L-OHP）的化疗敏感性。本研究表明，自噬在HY-PDT过程中的化学增敏作用中起关键作用。我们证明促死亡自噬是致敏和HY-PDT/L-OHP抗肿瘤协同作用所必需的。高剂量的HY-PDT诱导自噬性细胞死亡；而低剂量的HY-PDT主要触发保护性自噬并促进细胞增殖。低剂量的HY-PDT降低了奥沙利铂耐药结肠癌细胞中L-OHP的细胞毒性。因此，不同水平的自噬导致了HY-PDT对细胞命运和化疗敏感性的相反作用。此外，我们揭示了CHOP作为内质网损伤下连接促生存和促死亡自噬的调节因子的作用。高剂量的HY-PDT诱导大量活性氧生成和严重的内质网应激，进而导致CHOP的诱导。CHOP从而激活CHOP/TRIB3/Akt/mTOR级联反应并触发自噬性细胞死亡。此外，当凋亡途径被阻断时，用高剂量HY-PDT处理的细胞优先通过自噬途径死亡。另一方面，自噬的抑制使细胞在低剂量HY-PDT下更容易发生凋亡。这些结果为内质网靶向光动力疗法在调节结直肠癌治疗化疗敏感性方面的临床应用提供了新的证据。
