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RhoB is required to mediate apoptosis in neoplastically transformed cells after DNA damage
Liu Ax1, G J Cerniglia, E J Bernhard
1The Wistar Institute, Philadelphia, PA 19104, USA.
Abstract:
The effect of neoplastic transformation on the response to genotoxic stress is of significant clinical interest. In this study, we offer genetic evidence that the apoptotic response of neoplastically transformed cells to DNA damage requires RhoB, a member of the Rho family of actin cytoskeletal regulators. Targeted deletion of the rhoB gene did not affect cell cycle arrest in either normal or transformed cells after exposure to doxorubicin or gamma irradiation, but rendered transformed cells resistant to apoptosis. This effect was specific insofar as rhoB deletion did not affect apoptotic susceptibility to agents that do not damage DNA. However, rhoB deletion also affected apoptotic susceptibility to Taxol, an agent that disrupts microtubule dynamics. We have demonstrated that RhoB alteration mediates the proapoptotic and antineoplastic effects of farnesyltransferase inhibitors, and we show here that RhoB alteration is also crucial for farnesyltransferase inhibitors to sensitize neoplastic cells to DNA damage-induced cell death. We found RhoB to be an important determinant of long-term survival in vitro and tumor response in vivo after gamma irradiation. Our findings identify a pivotal role for RhoB in the apoptotic response of neoplastic cells to DNA damage at a novel regulatory point that may involve the actin cytoskeleton.
Insights
Neoplastic cells require RhoB (a protein regulating the actin cytoskeleton) for apoptosis after DNA damage. RhoB deletion confers resistance to genotoxic stress-induced cell death, impacting cancer cell survival.
Area of Science:
- Cell Biology
- Cancer Research
- Molecular Oncology
Background:
- Neoplastic transformation alters cellular responses to genotoxic stress, a critical factor in cancer progression and treatment.
- Understanding the molecular mechanisms governing apoptosis in cancer cells is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the role of RhoB, a regulator of the actin cytoskeleton, in the apoptotic response of neoplastic cells to DNA damage.
- To determine if RhoB is essential for sensitizing cancer cells to genotoxic agents and farnesyltransferase inhibitors.
Main Methods:
- Targeted deletion of the rhoB gene in neoplastic cells.
- Exposure to genotoxic agents (doxorubicin, gamma irradiation) and non-DNA damaging agents.
- Assessment of cell cycle arrest and apoptosis.
- Evaluation of RhoB's role in mediating the effects of farnesyltransferase inhibitors.
- In vitro and in vivo studies of tumor response to gamma irradiation.
Main Results:
- RhoB deletion did not affect cell cycle arrest but rendered transformed cells resistant to DNA damage-induced apoptosis.
- RhoB deletion did not alter apoptosis induced by non-DNA damaging agents but affected susceptibility to Taxol.
- RhoB alteration is critical for farnesyltransferase inhibitors to sensitize neoplastic cells to DNA damage.
- RhoB is a key determinant of long-term survival and tumor response after gamma irradiation.
Conclusions:
- RhoB plays a pivotal role in the apoptotic response of neoplastic cells to DNA damage.
- RhoB acts at a novel regulatory point, potentially involving the actin cytoskeleton, in cancer cell death pathways.
- Targeting RhoB may represent a therapeutic strategy to enhance cancer cell sensitivity to genotoxic stress and other treatments.