Hexavalent chromium induced autophagy-dependent mTOR expression mediated by upregulation of HMGA2.

High mobility group A2 (HMGA2) overexpression is often observed in cancers. Previously, we found that HMGA2 contributed to hexavalent chromium [Cr (VI)]-mediated autophagy. In this study, interestingly, Cr (VI) treatment triggered both autophagy and the mammalian target of rapamycin (mTOR) in vivo ( BALB/c mice, 0.5 and 1.5 mg/kg, p.o.) and in vitro (0.1, 0.2 and 0.4 μM in A549 and HELF cells), and both autophagy and mTOR were implicated in Cr (VI)-initiated cell growth. Autophagy and mTOR were both significantly induced by HMGA2 overexpression in vivo (BALB/c mice were intratracheal injected with 10 μg and 20 μg pcDNA3.1-HMGA2 plasmid complexes) and in vitro (A549 and HELF cells). Using the autophagy suppressor, 3-methyladenine (3MA, 2 mM), chloroquine (CQ, 10 μM), and knockdown of autophagy-related protein 4 homolog B (ATG4B) gene by siRNA, it was shown that Cr (VI)-provoked mTOR was reliant on autophagy. Furthermore, the results of the scratch assay indicated that HMGA2-mediated cell migration depends on autophagy, mTOR, and glycolysis. Chromatin immunoprecipitation assay elucidated elective binding of HMGA2 protein to the ATG4B promoter region, but not AKT1 and mTOR. Altogether, our findings demonstrated that both autophagy and mTOR could be induced by Cr (VI) and they were involved in Cr (VI)-caused cell growth and migration. HMGA2 mediated this effect by transcription regulation of ATG4B. These suggested that blocking the HMGA2-autophagy-mTOR axis could serve as an effective strategy to inhibit Cr (VI)-induced cell viability.