High-fat diet feeding and palmitic acid increase CRC growth in β2AR-dependent manner.
Adrenergic beta-Agonists
/ pharmacology
Animals
Cell Line, Tumor
Cell Proliferation
/ drug effects
Colorectal Neoplasms
/ enzymology
Computational Biology
Cyclic AMP-Dependent Protein Kinases
/ genetics
Diet, High-Fat
/ adverse effects
Disease Models, Animal
Humans
Lipid Metabolism
/ drug effects
Male
Mice
Mice, Nude
Palmitic Acid
/ metabolism
Phosphorylation
RNA, Small Interfering
Receptors, Adrenergic, beta
/ genetics
Signal Transduction
/ drug effects
Sp1 Transcription Factor
/ genetics
Stearic Acids
/ metabolism
Sterol Esterase
/ chemistry
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
26 09 2019
26 09 2019
Historique:
received:
28
03
2019
accepted:
05
09
2019
revised:
26
08
2019
entrez:
28
9
2019
pubmed:
29
9
2019
medline:
28
8
2020
Statut:
epublish
Résumé
Epidemiology studies indicate that consumption of high-fat diet (HFD) is directly associated with the development of colorectal cancer (CRC). However, the exact component in HFD and the mechanism underlying its effect on CRC growth remained unclear. Our study shows that HFD feeding increases β2AR expression in the xenograft tissues of CRC-bearing mouse model; the elevated β2AR expression is reduced when HFD is replaced by control diet, which strongly suggests an association between HFD feeding and β2AR expression in CRC. HFD feeding increases palmitic acid and stearic acid levels in CRC; however, only palmitic acid increases β2AR expression, which is dependent upon Sp1. β2AR plays the dominant role in promoting CRC cell proliferation among all the β-AR subtypes. More importantly, knockout of β2AR or knockdown of Sp1 abolishes the palmitic acid increased CRC cell proliferation, suggesting palmitic acid increases CRC cell proliferation in β2AR-dependent manner. HFD or palmitic acid-rich diet (PAD) also fails to increase the tumor growth in xenograft mouse models bearing β2AR-knockout CRC cells. β2AR promotes CRC growth by increasing the phosphorylation of HSL at the residue S552. The phosphorylated and activated HSL (S552) changes the metabolic phenotype of CRC and increases energy production, which promotes CRC growth. Our study has revealed the unique tumorigenic properties of palmitic acid in promoting CRC growth, and have delineated the underlying mechanism of action. We are also the first to report the linkage between HFD feeding and β-adrenergic signaling pathway in relation to CRC growth.
Identifiants
pubmed: 31558710
doi: 10.1038/s41419-019-1958-6
pii: 10.1038/s41419-019-1958-6
pmc: PMC6763436
doi:
Substances chimiques
Adrenergic beta-Agonists
0
RNA, Small Interfering
0
Receptors, Adrenergic, beta
0
Sp1 Transcription Factor
0
SP1 protein, human
0
Stearic Acids
0
Palmitic Acid
2V16EO95H1
stearic acid
4ELV7Z65AP
Cyclic AMP-Dependent Protein Kinases
EC 2.7.11.11
Sterol Esterase
EC 3.1.1.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
711Références
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