H2O2 treatment or serum deprivation induces autophagy and apoptosis in naked mole-rat skin fibroblasts by inhibiting the PI3K/Akt signaling pathway

// Shanmin Zhao 1, * , Li Li 2, * , Shiyong Wang 3, * , Chenlin Yu 1 , Bang Xiao 1 , Lifang Lin 1 , Wei Cong 1 , Jishuai Cheng 1 , Wenjing Yang 1 , Wei Sun 1 , Shufang Cui 1 1 Laboratory Animal Centre, Second Military Medical University, Shanghai, China 2 Department of Training, Second Military Medical University, Shanghai, China 3 Informatization Office, Second Military Medical University, Shanghai, China * These authors contributed equally to this work Correspondence to: Shufang Cui, email: [email protected] Keywords: naked mole-rats, autophagy(definition), apoptosis Received: August 05, 2016      Accepted: October 28, 2016      Published: November 12, 2016 ABSTRACT Naked mole-rats (NMR; Heterocephalus glaber ) display extreme longevity and resistance to cancer. Here, we examined whether autophagy contributes to the longevity of NMRs by assessing the effects of the PI3K/Akt pathway inhibitor LY294002 and the autophagy inhibitor chloroquine (CQ) on autophagy and apoptosis in NMR skin fibroblasts. Serum starvation, H2O2 treatment, and LY294002 treatment all increased the LC3-II/LC3-I ratio and numbers of double-membraned autophagosomes and autophagic vacuoles, and decreased levels of p70S6K, p-Akt Ser473 , and p-Akt Thr308 . By contrast, CQ treatment decreased p70S6K, Akt Ser473 , and Akt Thr308 levels. The Bax/Bcl-2 ratio increased after 12 h of exposure to LY294002 or CQ. These data show that inhibiting the Akt pathway promotes autophagy and apoptosis in NMR skin fibroblasts. Furthermore, LY294002 or CQ treatment decreased caspase-3, p53, and HIF1-α levels, suggesting that serum starvation or H2O2 treatment increase autophagy and apoptosis in NMR skin fibroblasts by inhibiting the PI3K/Akt pathway. CQ-induced inhibition of late autophagy stages also prevented Akt activation and induced apoptosis. Finally, the HIF-1α and p53 pathways were involved in serum starvation- or H2O2-induced autophagy in NMR skin fibroblasts.