Faculty Collaboration Database

Modulatory effect of curcumin on survival of irradiated human intestinal microvascular endothelial cells: role of Akt/mTOR and NF-{kappa}B. Am J Physiol Gastrointest Liver Physiol 2010 Jun;298(6):G865-77

Date

03/20/2010

Pubmed ID

20299603

Pubmed Central ID

PMC3774333

DOI

10.1152/ajpgi.00339.2009

Scopus ID

2-s2.0-77952739880 (requires institutional sign-in at Scopus site)   43 Citations

Abstract

Radiation therapy is an essential modality in the treatment of colorectal cancers. Radiation exerts an antiangiogenic effect on tumors, inhibiting endothelial proliferation and survival in the tumor microvasculature. However, damage from low levels of irradiation can induce a paradoxical effect, stimulating survival in endothelial cells. We used human intestinal microvascular endothelial cells (HIMEC) to define effects of radiation on these gut-specific endothelial cells. Low-level irradiation (1-5 Gy) activates NF-kappaB and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is involved in cell cycle reentry and cell survival in HIMEC. A downstream target of PI3K/Akt is mammalian target of rapamycin (mTOR), which contributes to endothelial proliferation and angiogenesis. The aim of this study was to investigate the signaling molecules involved in the radiosensitizing effects of curcumin on HIMEC subjected to low levels of irradiation. We have demonstrated that exposure of HIMEC to low levels of irradiation induced Akt and mTOR phosphorylation, which was attenuated by curcumin, rapamycin, LY294002, and mTOR small interference RNA (siRNA). Activation of NF-kappaB by low levels of irradiation was inhibited by curcumin, SN-50, and mTOR siRNA. Curcumin also induced apoptosis by induction of caspase-3 cleavage in irradiated HIMEC. In conclusion, curcumin significantly inhibited NF-kappaB and attenuated the effect of irradiation-induced prosurvival signaling through the PI3K/Akt/mTOR and NF-kappaB pathways in these gut-specific endothelial cells. Curcumin may be a potential radiosensitizing agent for enhanced antiangiogenic effect in colorectal cancer radiation therapy.

Author List

Rafiee P, Binion DG, Wellner M, Behmaram B, Floer M, Mitton E, Nie L, Zhang Z, Otterson MF

Author

Mary F. Otterson MD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Abnormalities, Radiation-Induced
Animals
Caspase 3
Cell Death
Cell Survival
Curcumin
Dose-Response Relationship, Drug
Endothelial Cells
Forkhead Box Protein O1
Forkhead Transcription Factors
Gene Expression Regulation
Gene Silencing
Humans
Intestines
Intracellular Signaling Peptides and Proteins
Male
Microvessels
NF-kappa B
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-mdm2
RNA, Small Interfering
Radiation-Sensitizing Agents
Rats
Rats, Sprague-Dawley
TOR Serine-Threonine Kinases