AMBRA1 and its role as a target for anticancer therapy

Abstract

The activating molecule in Beclin1-regulated autophagy protein 1 (AMBRA1) is an intrinsically disordered protein that regulates the survival and death of cancer cells by modulating autophagy. Although the roles of autophagy in cancer are controversial and context-dependent, inhibition of autophagy under some circumstances can be a useful strategy for cancer therapy. As AMBRA1 is a pivotal autophagy-associated protein, targeting AMBRA1 similarly may be an underlying strategy for cancer therapy. Emerging evidence indicates that AMBRA1 can also inhibit cancer formation, maintenance, and progression by regulating c-MYC and cyclins, which are frequently deregulated in human cancer cells. Therefore, AMBRA1 is at the crossroad of autophagy, tumorigenesis, proliferation, and cell cycle. In this review, we focus on discussing the mechanisms of AMBRA1 in autophagy, mitophagy, and apoptosis, and particularly the roles of AMBRA1 in tumorigenesis and targeted therapy.

Role of Dietary Factors on DNA Methylation Levels of TNF-Alpha Gene and Proteome Profiles in Obese Men

“…AMBRA1 has been reported to have various functions in carcinogenesis, including autophagy, tumorigenesis, proliferation, and the cell cycle. Emerging evidence has indicated that AMBRA1 affects cancer formation, maintenance, and progression by regulating c-MYC and cyclins, which are frequently deregulated in human cancer cells [ 42 ]. CACNA1A is a protein in voltage-dependent Ca 2+ channels that controls the entry of Ca 2+ into excitable cells and regulates BP through vascular smooth muscle contraction [ 43 ].…”

Structural basis for substrate recruitment by AMBRA1 E3 ligase receptor

“…These reported regions locate at the intrinsically disordered regions linking WD40-N and WD40-C, and C-terminus. Furthermore, the N-terminal and C-terminal regions of AMBRA1 are involved in interaction with BCL-2, ULK1, ELONGIN B and PARKIN, however the precise interaction sites are not known [29]. In order to gain insights how these regions are organized relative to AMBRA1 WD40 domain in CRL4 structure, we superimposed the Alphafold2 model of AMBRA1 which retains all the loops to our CRL4-AMBRA1 structural model ( Fig.…”

Chinese botanical drugs targeting mitophagy to alleviate diabetic kidney disease, a comprehensive review

“…As well, AMBRA1 has a significant role in apoptosis as an autophagy-associated protein and a direct substrate for cystathionin and calpain ( Maria Fimia et al, 2007 ). During the stage of autophagy induction, AMBRA1 is capable of modulating ULK1 kinase activity, as well as interacting with BECLIN1 and VPS34 to manage relevant activities ( Li X. et al, 2022 ). Under normal conditions, AMBRA1 has a preference to interact with mitochondrial BCL-2 (mito-BCL-2), and when mitophagy is activated, the interaction between AMBRA1 and mito-BCL-2 is broken ( Strappazzon et al, 2011 ).…”