Abstract
A significant variation in susceptibility to paclitaxel-mediated killing was observed among a panel of short-term cultured non-small-cell lung cancer (NSCLC) cell lines. Susceptibility to killing by paclitaxel correlated with expression of the BH3-only protein, Bim, but not with other members of Bcl-2 family. NSCLC cell lines with the highest level of Bim expression are most susceptible to apoptosis induction after paclitaxel treatment. Forced expression of Bim increased paclitaxel-mediated killing of cells expressing an undetectable level of Bim. Conversely, knock down of Bim, but not Bcl-2 expression, decreased the susceptibility of tumor cells to paclitaxel-mediated killing. Similar observations were made using a panel of breast and prostate cancer cell lines. Paclitaxel impairs microtubule function, causes G2/M cell cycle blockade, mitochondria damage, and p53-independent apoptosis. These results established Bim as a critical molecular link between the microtubule poison, paclitaxel, and apoptosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Carcinoma, Non-Small-Cell Lung
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Caspase Inhibitors
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Caspases / metabolism
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Cell Division / drug effects
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Cell Line, Tumor
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Enzyme Activation
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Female
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G2 Phase / drug effects
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Humans
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Lung Neoplasms
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Microtubules / drug effects
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Microtubules / physiology
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Mitochondria / drug effects
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Mitochondria / metabolism
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Paclitaxel / pharmacology*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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RNA, Small Interfering / metabolism
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Signal Transduction
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Tumor Suppressor Protein p53 / metabolism
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Carrier Proteins
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Caspase Inhibitors
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Membrane Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Tumor Suppressor Protein p53
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Caspases
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Paclitaxel