Endoplasmic reticulum stress induces epithelial-mesenchymal transition through autophagy via activation of c-Src kinase

Soo Young Moon, Hyo Sang Kim, Kyeong Woo Nho, Young Joo Jang, Sang Koo Lee
Nephron. Experimental Nephrology 2014, 126 (3): 127-40

BACKGROUND: Endoplasmic reticulum (ER) stress has been implicated in inducing epithelial-mesenchymal transition (EMT). ER stress is also known to induce autophagy. However, it is unclear whether ER stress-induced autophagy contributes to EMT. We hypothesized that ER stress might induce EMT through autophagy via activation of c-Src kinase in tubular epithelial cells.

METHOD: All experiments were performed using HK-2 cells. Protein expression was measured by Western blot analysis. Immunofluorescence and small interfering RNA (siRNA) experiments were performed.

RESULTS: Chemical ER stress inducers such as tunicamycin (TM, 0.2 μM) and thapsigargin (TG, 0.2 μM) induced EMT, as shown by upregulation of α-smooth muscle actin and downregulation of E-cadherin. ER stress inhibitors such as 4-PBA and salubrinal suppressed both TM- and TG-induced EMT. TM and TG also induced autophagy, as evidenced by upregulation of LC3-II and beclin-1, which were abolished by pretreatment with ER stress inhibitors. Transfection with siRNA targeting ER stress protein (IRE-1) blocked the TM- or TG-induced EMT and autophagy. Autophagy inhibitors such as 3-methyladenine and bafilomycin inhibited the TM- or TG-induced EMT. Transfection with siRNA targeting autophagy protein (beclin-1) also blocked the TM- or TG-induced EMT. Both TM and TG induced activation of c-Src kinase. Inhibitor of c-Src kinase (PP2) suppressed the TM- or TG-induced autophagy and EMT.

CONCLUSION: ER stress by TM or TG induced EMT through autophagy via activation of c-Src kinase in tubular epithelial cells.

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