5-Methoxyflavanone induces cell cycle arrest at the G2/M phase, apoptosis and autophagy in HCT116 human colon cancer cells

Journal Article · Mon Aug 01 04:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.05.003· OSTI ID:21587798

Shin, Soon Young ^[1]; Hyun, Jiye ^[2]; Yu, Jae-Ran ^[3]; Lim, Yoongho ^[2]

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1. SMART Institute of Advanced Biomedical Science, Konkuk University Medical Center, Seoul 143-701 (Korea, Republic of)
2. Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul 143-701 (Korea, Republic of)
3. Department of Environmental and Tropical Medicine, Konkuk University School of Medicine, Seoul 143-701 (Korea, Republic of)

Natural flavonoids have diverse pharmacological activities, including anti-oxidative, anti-inflammatory, and anti-cancer activities. In this study, we investigated the molecular mechanism underlying the action of 5-methoxyflavanone (5-MF) which has a strong bioavailability and metabolic stability. Our results show that 5-MF inhibited the growth and clonogenicity of HCT116 human colon cancer cells, and that it activated DNA damage responses, as revealed by the accumulation of p53 and the phosphorylation of DNA damage-sensitive proteins, including ataxia-telangiectasia mutated (ATM) at Ser1981, checkpoint kinase 2 (Chk2) at Thr68, and histone H2AX at Ser139. 5-MF-induced DNA damage was confirmed in a comet tail assay. We also found that 5-MF increased the cleavage of caspase-2 and -7, leading to the induction of apoptosis. Pretreatment with the ATM inhibitor KU55933 enhanced 5-MF-induced {gamma}-H2AX formation and caspase-7 cleavage. HCT116 cells lacking p53 (p53{sup -/-}) or p21 (p21{sup -/-}) exhibited increased sensitivity to 5-MF compared to wild-type cells. 5-MF further induced autophagy via an ERK signaling pathway. Blockage of autophagy with the MEK inhibitor U0126 potentiated 5-MF-induced {gamma}-H2AX formation and caspase-2 activation. These results suggest that a caspase-2 cascade mediates 5-MF-induced anti-tumor activity, while an ATM/Chk2/p53/p21 checkpoint pathway and ERK-mediated autophagy act as a survival program to block caspase-2-mediated apoptosis induced by 5-MF. - Graphical abstract: Display Omitted Highlights: > 5-MF inhibits the proliferation of HCT116 colon cancer cells. > 5-MF inhibits cell cycle progression and induces apoptosis. > Inhibition of autophagy triggers 5-MF-induced apoptosis. > Inhibition of ERK signaling blocks 5-MF-induced autophagy but activates apoptosis. > Treatment with 5-MF in combination with an ERK inhibitor may be a potential therapeutic strategy in human colon cancer.

• OSTI ID: 21587798
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 254; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
BIOLOGICAL AVAILABILITY
BODY
CELL CYCLE
CHEMICAL REACTIONS
CLEAVAGE
DIGESTIVE SYSTEM
DISEASES
DNA DAMAGES
FLAVONOIDS
GASTROINTESTINAL TRACT
INFLAMMATION
INHIBITION
INTESTINES
LARGE INTESTINE
MICROSTRUCTURE
NEOPLASMS
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
OXIDATION
PATHOLOGICAL CHANGES
PHOSPHORYLATION
SENSITIVITY
SYMPTOMS