AMBRA1 and Its Role As a Target for Anticancer Therapy

Overview

Journal Front Oncol

Specialty Oncology

Date 2022 Oct 14

PMID 36237336

Authors

Xiang Li

Yuan Lyu

Junqi Li

Xinjun Wang

Affiliations

Soon will be listed here.

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.

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References

Friedman R, Farh K, Burge C, Bartel D . Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2008; 19(1):92-105. PMC: 2612969. DOI: 10.1101/gr.082701.108. View

Verfaillie T, Salazar M, Velasco G, Agostinis P . Linking ER Stress to Autophagy: Potential Implications for Cancer Therapy. Int J Cell Biol. 2010; 2010:930509. PMC: 2817393. DOI: 10.1155/2010/930509. View

Duffy M, OGrady S, Tang M, Crown J . MYC as a target for cancer treatment. Cancer Treat Rev. 2021; 94:102154. DOI: 10.1016/j.ctrv.2021.102154. View

Garofalo T, Matarrese P, Manganelli V, Marconi M, Tinari A, Gambardella L . Evidence for the involvement of lipid rafts localized at the ER-mitochondria associated membranes in autophagosome formation. Autophagy. 2016; 12(6):917-35. PMC: 4922444. DOI: 10.1080/15548627.2016.1160971. View

Kunz J, Schwarz H, Mayer A . Determination of four sequential stages during microautophagy in vitro. J Biol Chem. 2003; 279(11):9987-96. DOI: 10.1074/jbc.M307905200. View

Antonioli M, Pagni B, Vescovo T, Ellis R, Cosway B, Rollo F . HPV sensitizes OPSCC cells to cisplatin-induced apoptosis by inhibiting autophagy through E7-mediated degradation of AMBRA1. Autophagy. 2020; 17(10):2842-2855. PMC: 8526016. DOI: 10.1080/15548627.2020.1847444. View

Li X, Zhang L, Yu L, Wei W, Lin X, Hou X . shRNA-mediated AMBRA1 knockdown reduces the cisplatin-induced autophagy and sensitizes ovarian cancer cells to cisplatin. J Toxicol Sci. 2016; 41(1):45-53. DOI: 10.2131/jts.41.45. View

Fimia G, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S, Nardacci R . Ambra1 regulates autophagy and development of the nervous system. Nature. 2007; 447(7148):1121-5. DOI: 10.1038/nature05925. View

Cianfanelli V, De Zio D, Di Bartolomeo S, Nazio F, Strappazzon F, Cecconi F . Ambra1 at a glance. J Cell Sci. 2015; 128(11):2003-8. DOI: 10.1242/jcs.168153. View

10.

Nazio F, Strappazzon F, Antonioli M, Bielli P, Cianfanelli V, Bordi M . mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat Cell Biol. 2013; 15(4):406-16. DOI: 10.1038/ncb2708. View

11.

Cianfanelli V, Fuoco C, Lorente M, Salazar M, Quondamatteo F, Gherardini P . AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation. Nat Cell Biol. 2014; 17(1):20-30. PMC: 4976803. DOI: 10.1038/ncb3072. View

12.

Liu J, Yuan B, Cao J, Luo H, Gu S, Zhang M . AMBRA1 Promotes TGFβ Signaling via Nonproteolytic Polyubiquitylation of Smad4. Cancer Res. 2021; 81(19):5007-5020. DOI: 10.1158/0008-5472.CAN-21-0431. View

13.

Deter R, Baudhuin P, DE DUVE C . Participation of lysosomes in cellular autophagy induced in rat liver by glucagon. J Cell Biol. 1967; 35(2):C11-6. PMC: 2107130. DOI: 10.1083/jcb.35.2.c11. View

14.

Sun W, Wang L, Luo J, Zhu H, Cai Z . Ambra1 inhibits paclitaxel-induced apoptosis in breast cancer cells by modulating the Bim/mitochondrial pathway. Neoplasma. 2019; 66(3):377-385. DOI: 10.4149/neo_2018_180710N467. View

15.

Chen S, Jang G, Huttenhain R, Gordon D, Du D, Newton B . CRL4 targets Elongin C for ubiquitination and degradation to modulate CRL5 signaling. EMBO J. 2018; 37(18). PMC: 6138441. DOI: 10.15252/embj.201797508. View

16.

Antonioli M, Albiero F, Nazio F, Vescovo T, Basulto Perdomo A, Corazzari M . AMBRA1 interplay with cullin E3 ubiquitin ligases regulates autophagy dynamics. Dev Cell. 2014; 31(6):734-46. DOI: 10.1016/j.devcel.2014.11.013. View

17.

Qian B, Pollard J . Macrophage diversity enhances tumor progression and metastasis. Cell. 2010; 141(1):39-51. PMC: 4994190. DOI: 10.1016/j.cell.2010.03.014. View

18.

Bhardwaj M, Leli N, Koumenis C, Amaravadi R . Regulation of autophagy by canonical and non-canonical ER stress responses. Semin Cancer Biol. 2019; 66:116-128. PMC: 7325862. DOI: 10.1016/j.semcancer.2019.11.007. View

19.

Majeski A, Dice J . Mechanisms of chaperone-mediated autophagy. Int J Biochem Cell Biol. 2004; 36(12):2435-44. DOI: 10.1016/j.biocel.2004.02.013. View

20.

Grimson A, Farh K, Johnston W, Garrett-Engele P, Lim L, Bartel D . MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell. 2007; 27(1):91-105. PMC: 3800283. DOI: 10.1016/j.molcel.2007.06.017. View