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Cited 32 time in webofscience Cited 39 time in scopus
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Crosstalk Between Apoptosis and Autophagy Is Regulated by the Arginylated BiP/Beclin-1/p62 Complex

Authors
Song, XinxinLee, Dae-HeeDilly, Ashok-KumarLee, Young-SunChoudry, Haroon AsifKwon, Yong TaeBartlett, 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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