The unique Akt inhibitor SC66 suppressed AMPK activity and abolished autophagy through the EGFR‐p62 pathway

Akt is usually considered to be a negative regulator of both autophagy and adenosine 5′‐monophosphate (AMP)‐activated protein kinase (AMPK) signaling. In the present study, we found that SC66, a pyridine‐based allosteric Akt inhibitor, suppressed basal and H2O2‐induced autophagy concurrent with decr...

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Veröffentlicht in:Cell biology international 2022-02, Vol.46 (2), p.311-322
Hauptverfasser: Hou, Bolin, Li, Erwei, Liang, Jingnan, Liu, Shuchun, Yang, Huaiyi, Liu, Ling, Jiang, Xuejun
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Sprache:eng
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Zusammenfassung:Akt is usually considered to be a negative regulator of both autophagy and adenosine 5′‐monophosphate (AMP)‐activated protein kinase (AMPK) signaling. In the present study, we found that SC66, a pyridine‐based allosteric Akt inhibitor, suppressed basal and H2O2‐induced autophagy concurrent with decreased phosphorylation and activity of AMPK. SC66 treatment led to the formation of a high molecular weight (HMW) form of SQSTM1/p62 (p62), which is an autophagic substrate and is essential for selective autophagy. Moreover, we observed that SC66 inhibited the binding of p62 and microtubule‐associated protein light chain 3 (LC3). The immunoprecipitation results revealed the interaction between p62 and epidermal growth factor receptor (EGFR), and knockdown of EGFR reversed SC66‐mediated autophagy inhibition without affecting the phosphorylation of acetyl‐CoA carboxylase (ACC), a well‐known substrate of AMPK. SC66 increased the interaction between EGFR and Beclin 1 and markedly decreased the association of EGFR with VPS34, a critical protein for autophagy induction. Collectively, the data presented here indicate that EGFR‐p62 pathway plays a critical role in Akt‐mediated positive regulation of autophagy.
ISSN:1065-6995
1095-8355
DOI:10.1002/cbin.11732