Related Experiment Videos
Inhibited transformation of immortalized human bronchial epithelial cells by retinoic acid is linked to cyclin E
J Langenfeld1, F Lonardo, H Kiyokawa
1Laboratory of Molecular Medicine, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Abstract:
The retinoids are reported to reduce second primary aerodigestive tract tumors in patients with prior lung or head and neck carcinomas. Yet, the optimal retinoid useful for chemoprevention and those mechanisms linked to this chemoprevention are not identified. This study reports an in vitro model for carcinogen-induced transformation of immortalized human bronchial epithelial (BEAS-2B) cells that was adapted to study the anti-carcinogenic effects of all-trans-retinoic acid (RA). Following exposure to carcinogens: cigarette smoke condensate (CSC) or N-nitrosamine-4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK), BEAS-2B cells exhibited evidence of transformation. This included an increased anchorage independent growth or acquired ability to form tumors in athymic mice. This transformation was inhibited by RA as demonstrated by a lack of augmented anchorage independent growth or tumor formation in athymic mice for the cells treated with RA. The BEAS-2B cells transformed by NNK exhibited an increase in cyclin E expression which was associated with an increase in the cyclin E-Cdk2 kinase activity. Over-expression of human cyclin E by transfection shows cyclin E enhances the basal clonal growth of BEAS-2B cells. In both the parental and transformed BEAS-2B cells, RA down-regulated cyclin E protein levels which was associated with an inhibition of growth and an accumulation of cells in G1. The data reported here suggest the decline of cyclin E expression represents a potential mechanism for the RA-induced growth suppression which is linked to the anti-carcinogenic effects of RA. Thus, this study reports the adaption of an in vitro model of lung carcinogenesis suitable to test the activity of chemoprevention agents.
Insights
All-trans-retinoic acid (RA) inhibits lung cancer cell growth by down-regulating cyclin E, offering a potential chemoprevention strategy. This study adapted an in vitro lung carcinogenesis model to test RA
Area of Science:
- Oncology
- Cell Biology
- Chemoprevention Research
Background:
- Retinoids show promise in preventing secondary aerodigestive tract tumors.
- Optimal retinoids and their chemoprevention mechanisms remain unclear.
Purpose of the Study:
- To establish an in vitro model for studying retinoid chemoprevention of lung cancer.
- To investigate the anti-carcinogenic mechanisms of all-trans-retinoic acid (RA).
Main Methods:
- Developed an in vitro model using immortalized human bronchial epithelial (BEAS-2B) cells.
- Induced cell transformation using cigarette smoke condensate (CSC) or NNK.
- Assessed the effects of RA on cell transformation, anchorage-independent growth, and tumor formation in mice.
- Analyzed changes in cyclin E expression and cyclin E-Cdk2 kinase activity.
Main Results:
- Carcinogen exposure (CSC, NNK) induced cell transformation, evidenced by increased anchorage-independent growth and tumor formation.
- RA treatment inhibited carcinogen-induced cell transformation and tumor formation.
- NNK-transformed cells showed increased cyclin E expression and activity, promoting cell growth.
- RA down-regulated cyclin E levels, inhibiting cell growth and causing G1 cell cycle arrest.
Conclusions:
- RA exhibits anti-carcinogenic effects in lung epithelial cells, potentially via down-regulation of cyclin E.
- The developed in vitro model is suitable for evaluating chemoprevention agents against lung carcinogenesis.
- Cyclin E down-regulation is a potential mechanism underlying RA's growth-suppressive and anti-carcinogenic effects.