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Published on: December 19, 2019
Ha-Ras sensitizes transformed mouse skin cells to Anisomycin-induced apoptosis
Juan F Santibañez1, Claudia Hurtado
1Laboratorio de Biología Celular, Instituto de Nutrición y Tecnología de los Alimentos, INTA, Universidad de Chile, Casilla 138, Santiago 11, Chile. jfsantib@inta.cl
Abstract:
Efforts have been made to develop a chemoprevention that selectively triggers apoptosis in malignant cancer cells. Here, we demonstrated that a mutated Ha-Ras activity is required in Anisomycin-induced apoptosis in transformed keratinocytes. Anisomycin stimulates JNK activity and apoptosis in oncogenic Ha-Ras positive cells, but not in normal keratinocytes. This effect was demonstrated in stably transfected cells with dominant negative Ha-Ras, that protected transformed cells, and oncogenic Ha-Ras that sensitized non-transformed cells to Anisomycin-induced apoptosis. Lastly, the treatment of cells with inhibitors of the JNK displayed resistance to Anisomycin induced apoptosis. These data suggests that the oncogenic Ha-Ras is important for Anisomycin-induced JNK activation and apoptosis in transformed keratinocytes.
Insights
Oncogenic Ha-Ras activity is crucial for Anisomycin-induced apoptosis in cancer cells. This study reveals Anisomycin stimulates JNK activity and cell death specifically in cancer cells with mutated Ha-Ras.
Area of Science:
- Molecular Oncology
- Cell Biology
- Cancer Chemoprevention
Background:
- Developing chemopreventive agents that selectively induce apoptosis in malignant cells is a key research area.
- The role of specific cellular pathways in drug-induced apoptosis requires further elucidation.
Purpose of the Study:
- To investigate the role of mutated Ha-Ras activity in Anisomycin-induced apoptosis in transformed keratinocytes.
- To determine if Anisomycin selectively targets cancer cells via Ha-Ras signaling.
Main Methods:
- Utilized stably transfected keratinocytes expressing dominant-negative Ha-Ras and oncogenic Ha-Ras.
- Assessed Anisomycin's effect on JNK activity and apoptosis in normal and transformed cells.
- Employed JNK inhibitors to evaluate their impact on Anisomycin-induced apoptosis.
Main Results:
- Anisomycin induced JNK activation and apoptosis exclusively in oncogenic Ha-Ras-positive transformed keratinocytes.
- Dominant-negative Ha-Ras protected transformed cells from Anisomycin-induced apoptosis.
- Oncogenic Ha-Ras sensitized non-transformed cells to Anisomycin, while JNK inhibitors conferred resistance.
Conclusions:
- Oncogenic Ha-Ras activity is essential for Anisomycin-mediated JNK activation and apoptosis in transformed keratinocytes.
- Anisomycin demonstrates selective apoptosis-inducing properties in cancer cells dependent on Ha-Ras mutation status.
- Targeting the Ha-Ras/JNK pathway presents a potential strategy for cancer chemoprevention.
