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Overexpression of Mad transcription factor inhibits proliferation of cultured human hepatocellular carcinoma cells along with tumor formation in immunodeficient animals.
J Gene Med. 2000 Mar-Apr; 2(2):117-27.JG

Abstract

BACKGROUND

Dominant negative regulation of critical cell cycle molecules could perturb survival of cancer cells and help develop novel therapies.

METHODS

To perturb the activity of c-Myc, which regulates G0/G1 transitions, we overexpressed Mad1 protein with an adenoviral vector, AdMad. Studies were conducted with established cell lines, including HepG2, HuH-7 and PLC/PRF/5 liver cancer cells, RAT-1A embryonic fibroblasts and U373MG astrocytoma cells.

RESULTS

After AdMad-treatment, transduced cells exhibited decreased proliferation rates in culture conditions. RAT-1A embryonic fibroblasts and U373MG astrocytoma cells showed accumulations in G0/G1, whereas HepG2 and HuH-7 cells accumulated in G0/G1, and additionally in G2/M, albeit to a lesser extent. An in vitro assay using hepatocyte growth factor to stimulate proliferation in HuH-7 cells showed blunting of growth factor responsiveness, along with inhibition of cell cycle progression in AdMad-treated cells. No cytotoxicity was observed in AdMad-treated cells in culture, although cells lost clonogenic capacity in soft agar. In vivo assays using HepG2 cell tumors in immunodeficient mice showed that overexpression of AdMad prevented tumorigenesis.

CONCLUSIONS

These studies indicate roles of Mad in G2/M, as well as the potential of manipulating cell cycle controls for treating liver cancer.

Links

Publisher Full Text

Authors+Show Affiliations

Gagandeep S
Marion Bessin Liver Research Center, Comprehensive Cancer Research Center, and Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Ott M
No affiliation info available
Nisen PD
No affiliation info available
DePinho RA
No affiliation info available
Gupta S
No affiliation info available

MeSH

AdenoviridaeAnimalsBasic Helix-Loop-Helix Leucine Zipper Transcription FactorsCarcinoma, HepatocellularCell DivisionDNA-Binding ProteinsGene Transfer TechniquesGenetic VectorsHumansInterphaseLiver NeoplasmsMiceMice, SCIDRepressor ProteinsTranscription FactorsTumor Cells, Cultured

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10809145

Citation

Gagandeep, S, et al. "Overexpression of Mad Transcription Factor Inhibits Proliferation of Cultured Human Hepatocellular Carcinoma Cells Along With Tumor Formation in Immunodeficient Animals." The Journal of Gene Medicine, vol. 2, no. 2, 2000, pp. 117-27.
Gagandeep S, Ott M, Nisen PD, et al. Overexpression of Mad transcription factor inhibits proliferation of cultured human hepatocellular carcinoma cells along with tumor formation in immunodeficient animals. J Gene Med. 2000;2(2):117-27.
Gagandeep, S., Ott, M., Nisen, P. D., DePinho, R. A., & Gupta, S. (2000). Overexpression of Mad transcription factor inhibits proliferation of cultured human hepatocellular carcinoma cells along with tumor formation in immunodeficient animals. The Journal of Gene Medicine, 2(2), 117-27.
Gagandeep S, et al. Overexpression of Mad Transcription Factor Inhibits Proliferation of Cultured Human Hepatocellular Carcinoma Cells Along With Tumor Formation in Immunodeficient Animals. J Gene Med. 2000 Mar-Apr;2(2):117-27. PubMed PMID: 10809145.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Overexpression of Mad transcription factor inhibits proliferation of cultured human hepatocellular carcinoma cells along with tumor formation in immunodeficient animals. AU - Gagandeep,S, AU - Ott,M, AU - Nisen,P D, AU - DePinho,R A, AU - Gupta,S, PY - 2000/5/16/pubmed PY - 2000/7/15/medline PY - 2000/5/16/entrez SP - 117 EP - 27 JF - The journal of gene medicine JO - J Gene Med VL - 2 IS - 2 N2 - BACKGROUND: Dominant negative regulation of critical cell cycle molecules could perturb survival of cancer cells and help develop novel therapies. METHODS: To perturb the activity of c-Myc, which regulates G0/G1 transitions, we overexpressed Mad1 protein with an adenoviral vector, AdMad. Studies were conducted with established cell lines, including HepG2, HuH-7 and PLC/PRF/5 liver cancer cells, RAT-1A embryonic fibroblasts and U373MG astrocytoma cells. RESULTS: After AdMad-treatment, transduced cells exhibited decreased proliferation rates in culture conditions. RAT-1A embryonic fibroblasts and U373MG astrocytoma cells showed accumulations in G0/G1, whereas HepG2 and HuH-7 cells accumulated in G0/G1, and additionally in G2/M, albeit to a lesser extent. An in vitro assay using hepatocyte growth factor to stimulate proliferation in HuH-7 cells showed blunting of growth factor responsiveness, along with inhibition of cell cycle progression in AdMad-treated cells. No cytotoxicity was observed in AdMad-treated cells in culture, although cells lost clonogenic capacity in soft agar. In vivo assays using HepG2 cell tumors in immunodeficient mice showed that overexpression of AdMad prevented tumorigenesis. CONCLUSIONS: These studies indicate roles of Mad in G2/M, as well as the potential of manipulating cell cycle controls for treating liver cancer. SN - 1099-498X UR - https://www.unboundmedicine.com/medline/citation/10809145/Overexpression_of_Mad_transcription_factor_inhibits_proliferation_of_cultured_human_hepatocellular_carcinoma_cells_along_with_tumor_formation_in_immunodeficient_animals_ L2 - https://doi.org/10.1002/(SICI)1521-2254(200003/04)2:2<117::AID-JGM96>3.0.CO;2-X DB - PRIME DP - Unbound Medicine ER -