In:
PLOS Biology, Public Library of Science (PLoS), Vol. 19, No. 4 ( 2021-4-27), p. e3001197-
Abstract:
Renal cell carcinoma (RCC) is responsible for most cases of the kidney cancer. Previous research showed that low serum levels of cholesterol level positively correlate with poorer RCC-specific survival outcomes. However, the underlying mechanisms and functional significance of the role of cholesterol in the development of RCC remain obscure. 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) plays a pivotal role in RCC development as it is the key rate-limiting enzyme of the cholesterol biosynthetic pathway. In this study, we demonstrated that the inhibition of HMGCR could accelerate the development of RCC tumors by lactate accumulation and angiogenesis in animal models. We identified that the inhibition of HMGCR led to an increase in glycolysis via the regulated HSP90 expression levels, thus maintaining the levels of a glycolysis rate-limiting enzyme, pyruvate kinase M2 (PKM2). Based on these findings, we reversed the HMGCR inhibition-induced tumor growth acceleration in RCC xenograft mice by suppressing glycolysis. Furthermore, the coadministration of Shikonin, a potent PKM2 inhibitor, reverted the tumor development induced by the HMGCR signaling pathway.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001197
DOI:
10.1371/journal.pbio.3001197.g001
DOI:
10.1371/journal.pbio.3001197.g002
DOI:
10.1371/journal.pbio.3001197.g003
DOI:
10.1371/journal.pbio.3001197.g004
DOI:
10.1371/journal.pbio.3001197.g005
DOI:
10.1371/journal.pbio.3001197.g006
DOI:
10.1371/journal.pbio.3001197.s001
DOI:
10.1371/journal.pbio.3001197.s002
DOI:
10.1371/journal.pbio.3001197.s003
DOI:
10.1371/journal.pbio.3001197.s004
DOI:
10.1371/journal.pbio.3001197.s005
DOI:
10.1371/journal.pbio.3001197.s006
DOI:
10.1371/journal.pbio.3001197.s007
DOI:
10.1371/journal.pbio.3001197.s008
DOI:
10.1371/journal.pbio.3001197.s009
DOI:
10.1371/journal.pbio.3001197.r001
DOI:
10.1371/journal.pbio.3001197.r002
DOI:
10.1371/journal.pbio.3001197.r003
DOI:
10.1371/journal.pbio.3001197.r004
DOI:
10.1371/journal.pbio.3001197.r005
DOI:
10.1371/journal.pbio.3001197.r006
DOI:
10.1371/journal.pbio.3001197.r007
DOI:
10.1371/journal.pbio.3001197.r008
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2126773-X
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