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Genistein elicits pleiotropic molecular effects on head and neck cancer cells
S A Alhasan1, O Aranha, F H Sarkar
1Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Abstract:
Genistein (4,5,7-trihydroxyisoflavone) has been reported to induce cell cycle arrest and apoptosis in different cancer cell lines in vitro and to show antitumor activity against a variety of tumors in animal models. We have previously reported (S. A. Alhasan et al., Nutr. Cancer, 34:12-19, 1999; S. A. Alhasan et al., Int. J. Oncol., 16: 333-338, 2000) that genistein induces cell cycle arrest and apoptosis by up-regulating p21(WAF1) and Bax, and down-regulating cyclin B1 and Bcl-2 in a head and neck cancer cell line. However, the precise molecular mechanism(s) by which genistein elicits its effects on head and neck cancer cells still remains to be elucidated. In the present study, we report that genistein induces several specific molecular changes in head and neck cancer cells, such as down-regulation of c-erbB-2 expression, down-regulation of MMP-2 and MMP-9 secretion, inhibition of tumor cell invasion and down-regulation of nuclear factor-kappaB DNA binding activity. In addition, genistein inhibited the levels of phosphorylated Akt and the expression of 14-3-3 protein. Moreover, genistein induces telomere shortening in treated cells without affecting telomerase activity in vitro. We also observed that genistein inhibits the translocation of telomerase catalytic subunit [human telomerase reverse transcriptase (hTERT)] to the nucleus, which may result in telomere shortening, although the activity of telomerase is unaffected, along with the inhibition of metaphase spread of chromosomes. From these results, together with our previously published reports, (S. A. Alhasan et al., Nutr. Cancer, 34: 12-19, 1999; S. A. Alhasan et al., Int. J. Oncol., 16: 333-338, 2000) we conclude that genistein elicits pleiotropic molecular changes that resulting in the inhibition of cell growth and the induction of apoptotic cell death of head and neck cancer cells, which suggests that genistein may be useful as a chemotherapeutic and/or chemopreventive agent for head and neck cancer.
Insights
Genistein, a soy isoflavone, inhibits head and neck cancer cell growth and induces apoptosis through multiple molecular pathways. This research suggests genistein
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Genistein (4,5,7-trihydroxyisoflavone) shows in vitro and in vivo antitumor activity.
- Previous studies indicated genistein induces cell cycle arrest and apoptosis in head and neck cancer cells.
- The precise molecular mechanisms of genistein's action on head and neck cancer remain incompletely understood.
Purpose of the Study:
- To elucidate the specific molecular mechanisms by which genistein affects head and neck cancer cells.
- To investigate genistein's impact on key molecular targets involved in cancer progression.
- To evaluate genistein's potential as a chemotherapeutic or chemopreventive agent for head and neck cancer.
Main Methods:
- Analysis of gene expression (c-erbB-2) and protein levels (Akt, 14-3-3 protein).
- Assessment of matrix metalloproteinase (MMP-2, MMP-9) secretion and tumor cell invasion.
- Evaluation of nuclear factor-kappaB (NF-κB) DNA binding activity.
- Measurement of telomere length, telomerase activity, and human telomerase reverse transcriptase (hTERT) nuclear translocation.
- Analysis of chromosome metaphase spreads.
Main Results:
- Genistein down-regulated c-erbB-2 expression, MMP-2 and MMP-9 secretion, and NF-κB DNA binding activity.
- Genistein inhibited tumor cell invasion, reduced phosphorylated Akt levels, and decreased 14-3-3 protein expression.
- Genistein induced telomere shortening by inhibiting hTERT nuclear translocation without affecting telomerase activity, and inhibited metaphase spread of chromosomes.
Conclusions:
- Genistein induces pleiotropic molecular changes in head and neck cancer cells.
- These changes result in the inhibition of cell growth and induction of apoptotic cell death.
- Genistein shows promise as a chemotherapeutic and/or chemopreventive agent for head and neck cancer.