Crosstalk Between Apoptosis and Autophagy Is Regulated by the Arginylated BiP/Beclin-1/p62 Complex
- Authors
- Song, Xinxin; Lee, Dae-Hee; Dilly, Ashok-Kumar; Lee, Young-Sun; Choudry, Haroon Asif; Kwon, Yong Tae; Bartlett, David L.; Lee, Yong J.
- Issue Date
- Jul-2018
- Publisher
- AMER ASSOC CANCER RESEARCH
- Citation
- MOLECULAR CANCER RESEARCH, v.16, no.7, pp 1077 - 1091
- Pages
- 15
- Indexed
- SCI
SCIE
SCOPUS
- Journal Title
- MOLECULAR CANCER RESEARCH
- Volume
- 16
- Number
- 7
- Start Page
- 1077
- End Page
- 1091
- URI
- https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/34093
- DOI
- 10.1158/1541-7786.MCR-17-0685
- ISSN
- 1541-7786
1557-3125
- Abstract
- Emerging evidence demonstrates that autophagy and apoptosis are interconnected and their interplay greatly affects cell death. However, the key regulators in this crosstalk remain elusive. Therefore, the role of N-terminal arginylated BiP (R-BiP)/Beclin-1/p62 complex was examined in the crosstalk between apoptosis and autophagy during combination chemotherapy with mitomycin C and bortezomib using immunoblot, immunoprecipitation, and cellular imaging assays in wild-type (WT) and genetically engineered colorectal cancer cells. In addition, the tumoricidal efficacy of the combinatorial treatment in a nude mouse tumor xenograft model of colorectal cancer was assessed. Bortezomib combined with mitomycin C synergistically induced cytotoxicity and apoptosis rather than autophagy. Mechanistically, this combination inactivated Akt and subsequently induced Beclin-1 (BECN1) dephosphorylation at Ser 234/295. Dephos-phorylation of Beclin-1 resulted in increased cleavage of Beclin-1 and disruption of the R-BiP/Beclin-1/p62 complex, which led to switching autophagy to the synergistic induction of apoptosis. Importantly, the combination significantly suppressed LS174T intraperitoneal xenograft tumor growth, induced Akt inactivation and Beclin-1 cleavage, and decreased autophagy in vivo. Moreover, the tumoricidal efficacy of the combinatorial treatment was less effective, in vitro and in vivo, in HCT116 tumors harboring a Beclin-1 caspase 8 cleavage site mutant knock-in. Implications: This study uncovers that the R-BiP/Beclin-1/p62 complex has an important role in the crosstalk between apoptosis and autophagy. The results also propose how mono-drug resistance can be overcome using potent combinations to improve anticancer therapy.
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Collections - 3. Graduate School > Graduate School > 1. Journal Articles
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