title: Endoplasmic reticulum stress-induced resistance to doxorubicin is reversed by paeonol treatment in human hepatocellular carcinoma cells.
abstract: BACKGROUND
  Endoplasmic reticulum stress (ER stress) is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. Paeonol (Pae, 2-hydroxy-4-methoxyacetophenone), is a natural product extracted from the root of Paeonia Suffruticosa Andrew. Although Pae displays anti-neoplastic activity and increases the efficacy of chemotherapeutic drugs in various cell lines and in animal models, studies related to the effect of Pae on ER stress-induced resistance to chemotherapeutic agents in hepatocellular carcinoma (HCC) are poorly understood.
  
  
  RESULTS
  In this study, we investigated the effect of the endoplasmic reticulum (ER) stress response during resistance of human hepatocellular carcinoma cells to doxorubicin. Treatment with the ER stress-inducer tunicamycin (TM) before the addition of doxorubicin reduced the rate of apoptosis induced by doxorubicin. Interestingly, co-pretreatment with tunicamycin and Pae significantly increased apoptosis induced by doxorubicin. Furthermore, induction of ER stress resulted in increasing expression of COX-2 concomitant with inactivation of Akt and up-regulation of the pro-apoptotic transcription factor CHOP (GADD153) in HepG2 cells. These cellular changes in gene expression and Akt activation may be an important resistance mechanism against doxorubicin in hepatocellular carcinoma cells undergoing ER stress. However, co-pretreatment with tunicamycin and Pae decreased the expression of COX-2 and levels of activation of Akt as well as increasing the levels of CHOP in HCC cells.
  
  
  CONCLUSIONS
  Our results demonstrate that Pae reverses ER stress-induced resistance to doxorubicin in human hepatocellular carcinoma cells by targeting COX-2 mediated inactivation of PI3K/AKT/CHOP.
authors: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors: Lulu
authors: L
authors: Fan
authors: Bing
authors: B
authors: Song
authors: Guoping
authors: G
authors: Sun
authors: Tai
authors: T
authors: Ma
authors: Fei
authors: F
authors: Zhong
authors: Wei
authors: W
authors: Wei
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology*
chemical_list: D000098:Acetophenones; D000970:Antineoplastic Agents; C497249:DDIT3 protein, human; D014415:Tunicamycin; D051742:Transcription Factor CHOP; C013638:paeonol; D004317:Doxorubicin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D051057:Proto-Oncogene Proteins c-akt
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