Hexavalent chromium [Cr (VI)], which is widely found in occupational environments, is a recognized human carcinogen. In this study, the role of endoplasmic reticulum (ER) stress in Cr (VI)-induced crosstalk of apoptosis and autophagy was investigated. Cr (VI) resulted in ER stress by upregulating the expression of GRP78 and p-PERK. 4-Phenylbutyric acid (4PBA), an inhibitor of ER stress, reduced both Cr (VI)-induced apoptosis and autophagy, suggesting that ER stress played an important role in Cr (VI)-induced apoptosis and autophagy in A549 cells. Furthermore, Cr (VI)-induced apoptosis preceded autophagy. Z-VAD-FMK, the suppressor of apoptosis, repressed Cr (VI)-induced autophagy. Pretreatment with 3-MA, the inhibitor of autophagy, increased Cr (VI)-induced apoptosis. Exposure to Cr (VI) significantly reduced mitochondrial membrane potential (MMP) during Cr (VI) treatment for 6–12 h. However, Cr (VI)-reduced MMP rescued significantly after treatment with Cr (VI) for 24 h compared with that of 6 h and 12 h groups, suggesting that Cr (VI)-induced autophagy at 24 h might rescue Cr (VI)-induced decrease of MMP through engulfing damaged mitochondria and then inhibit apoptosis in A549 cells. Above all, our results indicated that Cr (VI)-induced ER stress plays an important role in the crosstalk between apoptosis and autophagy. The autophagy might be apoptosis-dependent and subsequently prevents apoptosis cell death to keep A549 cells resistant to Cr (VI)-induced further toxicity. This maybe underlies the mechanism of Cr (VI)-induced carcinogenesis.
