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Adenovirus E1a-mediated tumor suppression by a c-erbB-2/neu-independent mechanism
1La Jolla Cancer Research Foundation, California 92037, USA.
Abstract:
We reported previously that the adenovirus E1a gene reversed the transformed phenotype of one human melanoma and one fibrosarcoma cell line (S. Frisch, Proc. Natl. Acad. Sci. USA, 88: 9077-9081, 1991). To determine the generality of the tumor suppression effects of E1a, a diversity of tumor cell lines, including A204 rhabdomyosarcoma, RD rhabdomyosarcoma, Saos-2 osteosarcoma, NCI-H23 non-small cell lung carcinoma, MDA-MB435S breast carcinoma, and ras-transformed MDCK kidney epithelial cells, were infected with a retrovirus bearing the 12S E1a coding sequence. We demonstrate here that the expression of E1a severely reduced the anchorage-independent and tumorigenic growth of these cell lines without affecting their growth under normal culture conditions. The parental tumor cells used in this study did not overexpress c-erbB-2/neu, and E1a did not affect its expression in these cells. Thus, tumor suppression by E1a can operate in a wide variety of human tumor cells by c-erbB-2/neu-independent mechanisms. E1a also sensitized these cell lines to the cytotoxic effects of the anticancer drugs etoposide and cisplatin. The results suggest that E1a could prove useful for the gene therapy of a wide variety of human cancers.
Insights
The adenovirus E1a gene suppressed tumor growth in diverse cancer cells, independent of c-erbB-2/neu. E1a also enhanced chemotherapy effectiveness, suggesting potential for broad cancer gene therapy applications.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Previous studies showed adenovirus E1a gene reversed transformed phenotypes in specific human tumor cell lines.
- The E1a gene's tumor suppressive capabilities and mechanisms require further investigation across a broader range of cancer types.
Purpose of the Study:
- To evaluate the generality of adenovirus E1a's tumor suppression effects across diverse human tumor cell lines.
- To determine if E1a's tumor suppression is dependent on c-erbB-2/neu expression.
- To assess E1a's impact on tumor cell sensitivity to common anticancer drugs.
Main Methods:
- Infection of various human tumor cell lines (rhabdomyosarcoma, osteosarcoma, lung carcinoma, breast carcinoma, kidney epithelial cells) with a retrovirus encoding the 12S E1a sequence.
- Assessment of anchorage-independent growth and tumorigenic potential in E1a-expressing cells.
- Analysis of c-erbB-2/neu expression levels in parental and E1a-expressing cells.
- Evaluation of E1a-expressing cells' sensitivity to etoposide and cisplatin.
Main Results:
- Adenovirus E1a expression significantly reduced anchorage-independent and tumorigenic growth in all tested tumor cell lines.
- E1a did not affect tumor cell growth under normal culture conditions.
- E1a's tumor suppressive effects were independent of c-erbB-2/neu expression.
- E1a sensitized tumor cells to the cytotoxic effects of etoposide and cisplatin.
Conclusions:
- Adenovirus E1a exhibits broad-spectrum tumor suppressor activity across diverse human cancer types.
- E1a-mediated tumor suppression operates through c-erbB-2/neu-independent pathways.
- Adenovirus E1a enhances the efficacy of conventional chemotherapy, indicating its potential utility in gene therapy for various cancers.