Characterization of p21Ras-mediated apoptosis induced by protein kinase C inhibition and application to human tumor cell lines
Autor: | James S. Liou, Douglas V. Faller, James S. Chen |
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Rok vydání: | 2003 |
Předmět: |
Physiology
Farnesyltransferase medicine.medical_treatment Clinical Biochemistry Cell Apoptosis Glyceryl Ethers CHO Cells Membrane Potentials Proto-Oncogene Proteins p21(ras) Jurkat Cells Mice Nude mouse Cricetulus Cell Line Tumor Cricetinae medicine Animals Humans Enzyme Inhibitors Protein kinase C Protein Kinase C biology Growth factor Cell Biology biology.organism_classification Cell biology Mitochondria medicine.anatomical_structure Genes ras Cell culture Mutation biology.protein Cancer research NIH 3T3 Cells DNA fragmentation |
Zdroj: | Journal of cellular physiology. 198(2) |
ISSN: | 0021-9541 |
Popis: | Suppression of PKC activity can selectively induce apoptosis in cells expressing a constitutively activated p21Ras protein. We demonstrate that continued expression of p21Ras activity is required in PKC-mediated apoptosis because farnesyltransferase inhibitors abrogated the loss of viability in p21Ras-transformed cells occurring following PKC inhibition. Studies utilizing gene transfer or viral vectors demonstrate that transient expression of oncogenic p21Ras activity is sufficient for induction of apoptosis by PKC inhibition, whereas physiologic activation of p21Ras by growth factor is not sufficient to induce apoptosis. Mechanistically, the p21Ras-mediated apoptosis induced by PKC inhibition is dependent upon mitochondrial dysregulation, with a concurrent loss of mitochondrial membrane potential (ψm). Cyclosporine A, which prevented the loss of ψm, also inhibited HMG-induced DNA fragmentation in cells expressing an activated p21Ras. Induction of apoptosis by PKC inhibition in human tumors with oncogenic p21Ras mutations was demonstrated. Inhibition of PKC caused increased apoptosis in MIA-PaCa-2, a human pancreatic tumor line containing a mutated Ki–ras allele, when compared to HS766T, a human pancreatic tumor line with normal Ki–ras alleles. Furthermore, PKC inhibition induced apoptosis in HCT116, a human colorectal tumor line containing an oncogenic Ki–ras allele but not in a subline (Hke3) in which the mutated Ki–ras allele had been disrupted. The PKC inhibitor 1-O-hexadecyl-2-O-methyl-rac-glycerol (HMG), significantly reduced p21Ras-mediated tumor growth in vivo in a nude mouse MIA-PaCa-2 xenograft model. Collectively these studies suggest the therapeutic feasibility of targeting PKC activity in tumors expressing an activated p21Ras oncoprotein. J. Cell. Physiol. 198: 277–294, 2004. © 2003 Wiley-Liss, Inc. |
Databáze: | OpenAIRE |
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