Prospective impact of 5-FU in the induction of endoplasmic reticulum             stress, modulation of GRP78 expression and autophagy in Sk-Hep1 cells.
Hepatocellular carcinoma (HCC) is one of the most aggressive malignant diseases             and is highly resistant to conventional chemotherapy. Therefore, HCC requires             more effective prevention and treatment strategies. 5-fluorouracil (5-FU) remains             the most widely used chemotherapeutic drug for the treatment of gastrointestinal,             breast, head and neck, and ovarian cancers. In pursuit of a novel effective strategy,             we have evaluated the potential of 5-FU to promote endoplasmic reticulum (ER)             stress and autophagy in Sk-Hep1 HCC cells. We found that 5-FU profoundly induces             ER stress in Sk-Hep1 cells and upregulates p53 and activates CHOP/GADD153 and             caspase-12. Activation of CHOP/GADD153 and caspase-12 promotes mitochondrial cell             death in Sk-Hep1 cells followed by ER stress. Changes in calcium homeostasis and             the protein folding machinery cause stress in the ER, leading to apoptotic cell             death. Stress in the ER activates autophagy to remove the misfolded protein aggregates             and recover from the stress environment. Our study demonstrates that 5-FU-induced             ER stress suppresses autophagy and also downregulates GRP78 expression. Activation             of autophagy followed by ER stress facilitates the cell survival response. Therefore,             the inhibition of protective autophagy may provide a useful pharmacological target.             Taken together, these results indicate that 5-FU-induced ER stress activates the             mitochondrial apoptotic cell death pathway by downregulating GRP78 and protective             autophagy proteins in Sk-Hep1 cells, raising the possibility of using 5-FU as             a therapeutic agent to target human HCC.
Department of Microbiology, College of Natural Sciences, Pukyong                     National University, Busan 608-737, Republic of Korea.
Anandam Kasin
AK
Yadunandam
Jin-Soo
JS
Yoon
Yeong-Ae
YA
Seong
Chul-Woong
CW
Oh
Gun-Do
GD
Kim
D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000503:physiopathology; D053454:Caspase 12 / Q000096:biosynthesis / Q000378:metabolism; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008928:Mitochondria / Q000378:metabolism; D011446:Prospective Studies; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D016159:Tumor Suppressor Protein p53; D051742:Transcription Factor CHOP; D053454:Caspase 12; D002118:Calcium; D005472:Fluorouracil