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A bcl-xS adenovirus selectively induces apoptosis in transformed cells compared to normal mammary cells
V N Sumantran1, D S Lee, K M Woods Ignatoski
1Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor 48109-0942, USA.
Abstract:
Oncogenes which drive the cell cycle, such as c-myc, can sensitize cells to apoptosis. This suggests the possibility that the expression of genes such as bcl-2 or bcl-xL is required to inhibit apoptosis induced by oncogene expression. We hypothesized that inhibition of Bcl-2/Bcl-xL by the pro-apoptotic Bcl-xS protein, would result in selective induction of apoptosis in mammary carcinoma cells compared to their nontransformed counterparts. Therefore, we compared the effects of Bcl-xS expression delivered by a bcl-xS adenovirus (bcl-xS-Adv) vector, on viability and apoptosis of nontransformed versus transformed mammary epithelial cells. We report that c-myc-transformed murine mammary cells are extremely sensitive to apoptosis induced by the bcl-xS adenovirus (bcl-xS-Adv) vector, whereas immortalized, nontransformed murine mammary cells are relatively resistant to apoptosis induced by this vector. Likewise, human mammary epithelial cells transduced with c-erbB-2 were more sensitive to apoptosis induced by the bcl-xS vector than the nontransformed parental cells. Similar results were obtained when we tested the effects of bcl-xS adenoviral infection on primary normal human mammary epithelial cells and SUM-190 PT cells, (a c-erbB-2 over-expressing human mammary carcinoma cell line) grown on Matrigel. These data are consistent with the hypothesis that inhibition of Bcl-2/Bcl-xL can result in selective killing of cancer cells compared to their nontransformed counterparts.
Insights
The pro-apoptotic Bcl-xS protein selectively induces apoptosis in cancer cells by inhibiting Bcl-2/Bcl-xL. This targeted cell death offers a potential strategy for cancer therapy, sparing normal cells.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Oncogenes like c-myc promote cell cycle progression and can sensitize cells to apoptosis.
- The expression of anti-apoptotic proteins, such as B-cell lymphoma 2 (Bcl-2) and Bcl-extra large (Bcl-xL), is crucial for inhibiting oncogene-induced apoptosis.
- The pro-apoptotic protein Bcl-extra small (Bcl-xS) antagonizes Bcl-2 and Bcl-xL, suggesting its potential role in selective cancer cell apoptosis.
Purpose of the Study:
- To investigate whether the inhibition of Bcl-2/Bcl-xL by Bcl-xS leads to selective apoptosis induction in mammary carcinoma cells compared to their nontransformed counterparts.
- To compare the sensitivity of normal versus transformed mammary epithelial cells to apoptosis induced by Bcl-xS expression delivered via an adenovirus vector.
Main Methods:
- Utilized a bcl-xS adenovirus (bcl-xS-Adv) vector to deliver the Bcl-xS gene into mammary epithelial cells.
- Compared the viability and apoptosis rates of c-myc-transformed murine mammary cells versus immortalized, nontransformed murine mammary cells following bcl-xS-Adv infection.
- Assessed the effects of bcl-xS adenoviral infection on human mammary epithelial cells transduced with c-erbB-2 and on primary normal human mammary epithelial cells and SUM-190 PT cells.
Main Results:
- c-myc-transformed murine mammary cells exhibited extreme sensitivity to apoptosis induced by bcl-xS-Adv, while nontransformed cells were relatively resistant.
- Human mammary epithelial cells overexpressing c-erbB-2 were more susceptible to bcl-xS-induced apoptosis than their nontransformed parental cells.
- Similar selective apoptosis induction was observed in primary normal human mammary epithelial cells versus the c-erbB-2 over-expressing SUM-190 PT carcinoma cell line.
Conclusions:
- Inhibition of Bcl-2/Bcl-xL by Bcl-xS results in the selective induction of apoptosis in mammary carcinoma cells.
- These findings support the hypothesis that targeting Bcl-2/Bcl-xL can lead to selective killing of cancer cells while sparing normal cells.
- The Bcl-xS adenovirus vector demonstrates potential as a therapeutic agent for selective cancer cell apoptosis.