Therapeutic _targeting of Autophagy

doi:10.1016/j.ebiom.2016.10.034

Review

. 2016 Dec:14:15-23.

doi: 10.1016/j.ebiom.2016.10.034. Epub 2016 Oct 23.

Therapeutic _targeting of Autophagy

Christina G Towers¹, Andrew Thorburn²

Affiliations

¹ Department of Pharmacology, University of Colorado School of Medicine, 12801 E. 17th Ave, Aurora, CO 80045, USA.
² Department of Pharmacology, University of Colorado School of Medicine, 12801 E. 17th Ave, Aurora, CO 80045, USA. Electronic address: Andrew.Thorburn@ucdenver.edu.

PMID: 28029600
PMCID: PMC5161418
DOI: 10.1016/j.ebiom.2016.10.034

Review

Therapeutic _targeting of Autophagy

Christina G Towers et al. EBioMedicine. 2016 Dec.

. 2016 Dec:14:15-23.

doi: 10.1016/j.ebiom.2016.10.034. Epub 2016 Oct 23.

Authors

Christina G Towers¹, Andrew Thorburn²

Affiliations

¹ Department of Pharmacology, University of Colorado School of Medicine, 12801 E. 17th Ave, Aurora, CO 80045, USA.
² Department of Pharmacology, University of Colorado School of Medicine, 12801 E. 17th Ave, Aurora, CO 80045, USA. Electronic address: Andrew.Thorburn@ucdenver.edu.

PMID: 28029600
PMCID: PMC5161418
DOI: 10.1016/j.ebiom.2016.10.034

Abstract

Autophagy is a catabolic process that facilitates nutrient recycling via degradation of damaged organelles and proteins through lysosomal mediated degradation. Alterations in this complex, and tightly regulated process, lead to disease. Autophagy is widely accepted as cytoprotective against neurodegenerative diseases and a variety of clinical interventions are moving forward to increase autophagy as a therapeutic intervention. Autophagy has both positive and negative roles in cancer and this has led to controversy over whether or how autophagy manipulation should be attempted in cancer therapy. Nevertheless, cancer is the disease where most current activity in trying to manipulate autophagy for therapy is taking place and dozens of clinical trials are using autophagy inhibition with Chloroquine or Hydroxychloroquine in combination with other drugs for the treatment of multiple neoplasms. Here, we review recent literature implicating autophagy in neurodegenerative diseases and cancer and highlight some of the opportunities, controversies and potential pitfalls of therapeutically _targeting autophagy.

Keywords: Autophagy; Cancer; Clinical trials; Neurodegenerative disease.

PubMed Disclaimer

Figures

**Fig. 1**
Interventions that _target autophagy. Macroautophagy is controlled by nutrient availability via regulation by mTORC1, which under conditions of nutrient availability can inhibit the formation of Ulk1/2 complexes. Ulk complexes facilitate Beclin-1 complex formation and phagaphore initiation. Phagaphore elongation is then mediated by LC3-PE conjugation and ATG5-12 conjugation. Finally, double membrane autophagasomes fuse with lysosomes to form autophagolysosomes resulting in degradation of autophagosome contents by lysosomal hydrolases. A number of pharmacological and naturally occurring agents have been designed/discovered that _target this pathway allowing interventions that upregulate and down regulate autophagy.

See this image and copyright information in PMC

Cited by

Autophagy blockade synergistically enhances nanosonosensitizer-enabled sonodynamic cancer nanotherapeutics.
Zhou L, Huo M, Qian X, Ding L, Yu L, Feng W, Cui X, Chen Y. Zhou L, et al. J Nanobiotechnology. 2021 Apr 20;19(1):112. doi: 10.1186/s12951-021-00855-y. J Nanobiotechnology. 2021. PMID: 33879173 Free PMC article.
Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar Ataxias.
Buijsen RAM, Toonen LJA, Gardiner SL, van Roon-Mom WMC. Buijsen RAM, et al. Neurotherapeutics. 2019 Apr;16(2):263-286. doi: 10.1007/s13311-018-00696-y. Neurotherapeutics. 2019. PMID: 30607747 Free PMC article. Review.
Ergosterol peroxide from marine fungus Phoma sp. induces ROS-dependent apoptosis and autophagy in human lung adenocarcinoma cells.
Wu HY, Yang FL, Li LH, Rao YK, Ju TC, Wong WT, Hsieh CY, Pivkin MV, Hua KF, Wu SH. Wu HY, et al. Sci Rep. 2018 Dec 18;8(1):17956. doi: 10.1038/s41598-018-36411-2. Sci Rep. 2018. PMID: 30560887 Free PMC article.
Development and validation of a survival model for lung adenocarcinoma based on autophagy-associated genes.
Wang X, Yao S, Xiao Z, Gong J, Liu Z, Han B, Zhang Z. Wang X, et al. J Transl Med. 2020 Apr 1;18(1):149. doi: 10.1186/s12967-020-02321-z. J Transl Med. 2020. PMID: 32238163 Free PMC article.
In Vitro Cytotoxic Study of Euphorbia grantii Oliv. Aerial Parts against MCF-7 and MCF-7^ADR Breast Cancer Cell Lines: A Bioactivity-Guided Isolation.
Radi MH, El-Shiekh RA, El-Halawany AM, Al-Abd AM, Abdel-Sattar E. Radi MH, et al. ACS Omega. 2023 May 15;8(20):18299-18305. doi: 10.1021/acsomega.3c02091. eCollection 2023 May 23. ACS Omega. 2023. PMID: 37251150 Free PMC article.

See all "Cited by" articles

References

1. Akin D., Wang S.K., Habibzadegah-Tari P., Law B., Ostrov D., Li M., Yin X.-M., Kim J.-S., Horenstein N., Dunn W.A. A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy. 2014;10:2021–2035. - PMC - PubMed
1. Amaravadi R.K. Transcriptional regulation of autophagy in RAS-driven cancers. J. Clin. Invest. 2015;125:1393–1395. - PMC - PubMed
1. Arias E., Koga H., Diaz A., Mocholi E., Patel B., Cuervo A.M. Lysosomal mTORC2/PHLPP1/Akt regulate chaperone-mediated autophagy. Mol. Cell. 2015;59:270–284. - PMC - PubMed
1. Baginska J., Viry E., Berchem G., Poli A., Noman M.Z., Van Moer K., Medves S., Zimmer J., Oudin A., Niclou S.P., Bleackley R.C., Goping I.S., Chouaib S., Janji B. Granzyme B degradation by autophagy decreases tumor cell susceptibility to natural killer-mediated lysis under hypoxia. Proc. Natl. Acad. Sci. U. S. A. 2013;110:17450–17455. - PMC - PubMed
1. Bago R., Malik N., Munson M.J., Prescott A.R., Davies P., Sommer E., Shpiro N., Ward R., Cross D., Ganley I.G., Alessi D.R. Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream _target of class III phosphoinositide 3-kinase. Biochem. J. 2014;463:413–427. - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
- scite Smart Citations
Medical
- MedlinePlus Health Information

[1] Akin D., Wang S.K., Habibzadegah-Tari P., Law B., Ostrov D., Li M., Yin X.-M., Kim J.-S., Horenstein N., Dunn W.A. A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy. 2014;10:2021–2035. - PMC - PubMed

[2] Akin D., Wang S.K., Habibzadegah-Tari P., Law B., Ostrov D., Li M., Yin X.-M., Kim J.-S., Horenstein N., Dunn W.A. A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy. 2014;10:2021–2035. - PMC - PubMed

[3] Amaravadi R.K. Transcriptional regulation of autophagy in RAS-driven cancers. J. Clin. Invest. 2015;125:1393–1395. - PMC - PubMed

[4] Amaravadi R.K. Transcriptional regulation of autophagy in RAS-driven cancers. J. Clin. Invest. 2015;125:1393–1395. - PMC - PubMed

[5] Arias E., Koga H., Diaz A., Mocholi E., Patel B., Cuervo A.M. Lysosomal mTORC2/PHLPP1/Akt regulate chaperone-mediated autophagy. Mol. Cell. 2015;59:270–284. - PMC - PubMed

[6] Arias E., Koga H., Diaz A., Mocholi E., Patel B., Cuervo A.M. Lysosomal mTORC2/PHLPP1/Akt regulate chaperone-mediated autophagy. Mol. Cell. 2015;59:270–284. - PMC - PubMed

[7] Baginska J., Viry E., Berchem G., Poli A., Noman M.Z., Van Moer K., Medves S., Zimmer J., Oudin A., Niclou S.P., Bleackley R.C., Goping I.S., Chouaib S., Janji B. Granzyme B degradation by autophagy decreases tumor cell susceptibility to natural killer-mediated lysis under hypoxia. Proc. Natl. Acad. Sci. U. S. A. 2013;110:17450–17455. - PMC - PubMed

[8] Baginska J., Viry E., Berchem G., Poli A., Noman M.Z., Van Moer K., Medves S., Zimmer J., Oudin A., Niclou S.P., Bleackley R.C., Goping I.S., Chouaib S., Janji B. Granzyme B degradation by autophagy decreases tumor cell susceptibility to natural killer-mediated lysis under hypoxia. Proc. Natl. Acad. Sci. U. S. A. 2013;110:17450–17455. - PMC - PubMed

[9] Bago R., Malik N., Munson M.J., Prescott A.R., Davies P., Sommer E., Shpiro N., Ward R., Cross D., Ganley I.G., Alessi D.R. Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream _target of class III phosphoinositide 3-kinase. Biochem. J. 2014;463:413–427. - PMC - PubMed

[10] Bago R., Malik N., Munson M.J., Prescott A.R., Davies P., Sommer E., Shpiro N., Ward R., Cross D., Ganley I.G., Alessi D.R. Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream _target of class III phosphoinositide 3-kinase. Biochem. J. 2014;463:413–427. - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Therapeutic _targeting of Autophagy

Affiliations

Therapeutic _targeting of Autophagy

Authors

Affiliations

Abstract

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical