mTORC1-dependent TFEB nucleus translocation and pro-survival autophagy induced by zeolitic imidazolate framework-8

A great variety of nanoparticles are known to induce autophagy, leading to either pro-death or pro-survival consequences. Zeolitic imidazolate framework-8 (ZIF-8), a type of porous metal-organic framework (MOF) material and a promising drug delivery vector, reportedly showing excellent efficacy for cancer therapy. However, less attention was paid to the potential biological effect of ZIF-8 per se, and if so, how the effect impacts cell fate and therapy outcomes. Herein, we showed that ZIF-8 induced autophagy in HeLa cells, characterized by increased autophagosome formation without disruption of autophagic flux, in a dose- and time-dependent fashion. ZIF-8 also caused dephosphorylation of the transcription factor EB (TFEB) at serine-142 and serine-211, leading to nucleus translocation of TFEB, an event that promoted lysosome biogenesis and was necessary for autophagy induction. We further pinpointed the inhibition of mTORC1 as the critical events upstream of ZIF-8-elicited TFEB dephosphorylation and the subsequent nucleus translocation. Furthermore, autophagy induced by ZIF-8 promoted cell survival, as inhibiting autophagy by either 3-methyladenine (3-MA) or ATG5 knockdown significantly enhanced ZIF-8-elicited HeLa cell death. Most importantly, doxorubicin-encapsulated ZIF-8 (DOX@ZIF-8) also elicited strong pro-survival autophagy, and the co-delivery of an autophagic inhibitor (3-MA) dramatically enhanced the cytotoxicity of DOX@ZIF-8 in HeLa cells. Our results revealed the unique ability of ZIF-8, both in a free and drug-loaded form, to induce pro-survival autophagy in certain cancer cells, a finding with important implications for potential clinical studies that utilize ZIF-8 as the drug carrier.