Autophagy involvement in cadmium resistance through induction of multidrug resistance-associated protein and counterbalance of endoplasmic reticulum stress WI38 lung epithelial fibroblast cells.
Human multidrug-resistance associated protein (MRP1) is known as a cellular efflux pump of heavy metals and anticancer drugs. In our previous study, MRP was found to have involvement in cell protection against cadmium (Cd) toxicity through apoptosis interruption. The purpose of the present study was to investigate the molecular mechanism of MRP1 in Cd resistance. For this purpose, we developed Cd-resistant cells (RWI38) from WI38 human lung epithelial fibroblast cells, which showed a 4-fold resistance to Cd when compared to WI38 cells. WI38 cells elicited endoplasmic reticulum (ER) stress through RNA-dependent protein kinase-like ER kinase (PERK) and the eukaryotic translation initiation factor 2 alpha (eIF2alpha), Chop, and glucose-regulated protein (Grp78). RWI38 cells responding to Cd did not elicit ER stress or mitochondrial apoptosis, but induced autophagy, as demonstrated by Atg5 induction, LC3 conversion, and formation of GFP-LC3 dots. A pharmacological inhibitor of p38 downregulated Cd-induced Atg5 and LC3II. A pharmacological inhibitor of autophagy or silencing of atg5 dephosphorylated p38 and Akt, and downregulated MRP1 and procaspase-3. However, pharmacological inhibition or silencing of mrp-1 had no affect on Cd-induced phosphorylated p38 and LC3II. These data indicate that Cd induces autophagy in RWI38 cells through a mechanism that involves p38 activation, which is involved in cell protection through counterbalance of ER stress and MRP1 induction.
Lim
Sung-Chul
SC
Research Center for Resistant Cells, College of Medicine, Chosun University, Seosuk-dong, Dong-gu, Gwangju 501-759, Republic of Korea.
Hahm
Kyung-Soo
KS
Lee
Song-Hee
SH
Oh
Seon-Hee
SH
D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002104:Cadmium / Q000633:toxicity*; D002460:Cell Line; D004351:Drug Resistance; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002104:Cadmium; D000091342:Endoplasmic Reticulum Chaperone BiP; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C000717247:HSPA5 protein, human; C421109:multidrug resistance-associated protein 1