QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jpet.108.144113v1 329/1/112    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Oh, S.-H. Articles by Lim, S.-C. Search for Related Content PubMed PubMed Citation Articles by Oh, S.-H. Articles by Lim, S.-C.

CELLULAR AND MOLECULAR

Endoplasmic Reticulum Stress-Mediated Autophagy/Apoptosis Induced by Capsaicin (8-Methyl-N-vanillyl-6-nonenamide) and Dihydrocapsaicin is Regulated by the Extent of c-Jun NH₂-Terminal Kinase/Extracellular Signal-Regulated Kinase Activation in WI38 Lung Epithelial Fibroblast Cells

Research Center for Resistant Cells (S.-H.O., S.-C.L.) and Department of Pathology (S.-C.L.), College of Medicine, Chosun University, Gwangju, Korea

Endoplasmic reticulum (ER) stress causes cell survival or death, which is dependent on the type of cell and stimulus. Capsaicin (8-methyl-N-vanillyl-6-nonenamide) and its analog, dihydrocapsaicin (DHC), induced caspase-3-independent/-dependent signaling pathways in WI38 lung epithelial fibroblast cells. Here, we describe the molecular mechanisms induced by both chemicals. Exposure to capsaicin or DHC caused induction of p53, p21, and G₀/G₁ arrest. DHC induced massive cellular vacuolization by dilation of the ER and mitochondria. Classic ER stress inducers elicited the unfolded protein response (UPR) and up-regulation of microtubule-associated protein 1 light chain-3 (LC3) II. DHC induced ER stress by the action of heavy chain-binding protein, IRE1, Chop, eukaryotic initiation factor 2, and caspase-4 and, to a lesser level, by capsaicin treatment. DHC treatment induced autophagy that was blocked by 3-methyladenine (3MA) and accumulated by bafilomycin A1. Blocking of DHC-induced autophagy by 3MA enhanced apoptotic cell death that was completely inhibited by treatment of cells with benzyl-oxcarbonyl-Val-Ala-Asp-fluoromethyl ketone. Knockdown of Ire1 down-regulated the DHC-induced Chop and LC3II and enhanced caspase-3 activation. DHC induced rapid and high-sustained c-Jun NH₂-terminal kinase (JNK)/extracellular signal-regulated kinase (ERK) activation, but capsaicin induced transient activation of JNK/ERK. The JNK inhibitor SP600125 down-regulated the expression of IRE1, Chop, and LC3II induced by DHC, thapsigargin, and MG132 [N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal]. Pharmacological blockade or knockdown of ERK down-regulated LC3II. Capsaicin and DHC induced Akt phosphorylation, and the phosphatidylinositol 3-kinase inhibitors, wortmannin and LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride], induced autophagy via ERK activation. Our results indicate that the differential responses of capsaicin and DHC for cell protection are caused by the extent of the UPR and autophagy that are both regulated by the level of JNK and ERK activation.

Address correspondence to: Dr. Sung-Chul Lim, Department of Pathology, College of Medicine, Chosun University, 588 Seosuk-dong, Dong-gu, Gwangu 501-759, Korea. E-mail: sclim{at}chosun.ac.kr