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Axl inhibitor R428 induces apoptosis of cancer cells by blocking lysosomal acidification and recycling independent of Axl inhibition.
Am J Cancer Res. 2018; 8(8):1466-1482.AJ

Abstract

R428 (BGB324) is an anti-cancer drug candidate under clinical investigation. It inhibits the receptor tyrosine kinase Axl and induces apoptosis of many types of cancer cells, but the relationship between the two has not been well established. We investigated the molecular mechanisms of the R428-induced apoptosis and found that R428 induced extensive cytoplasmic vacuolization and caspase activation, independent of its inhibitory effects on Axl. Further analyses revealed that R428 blocked lysosomal acidification and recycling, accumulated autophagosomes and lysosomes, and induced cell apoptosis. Inhibition of autophagy by autophagy inhibitors or autophagic gene-knockout alleviated the R428-induced vacuoles formation and cell apoptosis. Our study uncovered a novel function and mechanism of R428 in addition to its ability to inhibit Axl. These data will help to better direct the application of R428 as an anti-cancer reagent. It also adds new knowledge to understand the regulation of autophagy and apoptosis.

Authors+Show Affiliations

Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai 201203, China. University of Chinese Academy of Sciences Beijing 100049, China.Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai 201203, China. University of Chinese Academy of Sciences Beijing 100049, China.Shanghai Institute of Materia Medica, Chinese Academy of Sciences Shanghai 201203, China. University of Chinese Academy of Sciences Beijing 100049, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30210917

Citation

Chen, Fangfang, et al. "Axl Inhibitor R428 Induces Apoptosis of Cancer Cells By Blocking Lysosomal Acidification and Recycling Independent of Axl Inhibition." American Journal of Cancer Research, vol. 8, no. 8, 2018, pp. 1466-1482.
Chen F, Song Q, Yu Q. Axl inhibitor R428 induces apoptosis of cancer cells by blocking lysosomal acidification and recycling independent of Axl inhibition. Am J Cancer Res. 2018;8(8):1466-1482.
Chen, F., Song, Q., & Yu, Q. (2018). Axl inhibitor R428 induces apoptosis of cancer cells by blocking lysosomal acidification and recycling independent of Axl inhibition. American Journal of Cancer Research, 8(8), 1466-1482.
Chen F, Song Q, Yu Q. Axl Inhibitor R428 Induces Apoptosis of Cancer Cells By Blocking Lysosomal Acidification and Recycling Independent of Axl Inhibition. Am J Cancer Res. 2018;8(8):1466-1482. PubMed PMID: 30210917.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Axl inhibitor R428 induces apoptosis of cancer cells by blocking lysosomal acidification and recycling independent of Axl inhibition. AU - Chen,Fangfang, AU - Song,Qiaoling, AU - Yu,Qiang, Y1 - 2018/08/01/ PY - 2018/06/05/received PY - 2018/07/09/accepted PY - 2018/9/14/entrez PY - 2018/9/14/pubmed PY - 2018/9/14/medline KW - Axl KW - R428 KW - apoptosis KW - autophagy KW - cancer cells KW - vacuolization SP - 1466 EP - 1482 JF - American journal of cancer research JO - Am J Cancer Res VL - 8 IS - 8 N2 - R428 (BGB324) is an anti-cancer drug candidate under clinical investigation. It inhibits the receptor tyrosine kinase Axl and induces apoptosis of many types of cancer cells, but the relationship between the two has not been well established. We investigated the molecular mechanisms of the R428-induced apoptosis and found that R428 induced extensive cytoplasmic vacuolization and caspase activation, independent of its inhibitory effects on Axl. Further analyses revealed that R428 blocked lysosomal acidification and recycling, accumulated autophagosomes and lysosomes, and induced cell apoptosis. Inhibition of autophagy by autophagy inhibitors or autophagic gene-knockout alleviated the R428-induced vacuoles formation and cell apoptosis. Our study uncovered a novel function and mechanism of R428 in addition to its ability to inhibit Axl. These data will help to better direct the application of R428 as an anti-cancer reagent. It also adds new knowledge to understand the regulation of autophagy and apoptosis. SN - 2156-6976 UR - https://www.unboundmedicine.com/medline/citation/30210917/Axl_inhibitor_R428_induces_apoptosis_of_cancer_cells_by_blocking_lysosomal_acidification_and_recycling_independent_of_Axl_inhibition_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30210917/ DB - PRIME DP - Unbound Medicine ER -
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