Bim is reversibly phosphorylated but plays a limited role in paclitaxel cytotoxicity of breast cancer cell lines.
The chemotherapeutic drug, paclitaxel, induces mitotic arrest and then activates the cellular apoptotic program. Although paclitaxel has been in clinical use for over 10 years for the treatment of breast, ovarian, and lung cancer, the molecular mechanisms of paclitaxel-induced cytotoxicity are ill defined. We decided to investigate the regulatory mechanism of the pro-apoptotic BH3-only protein Bim, which is known to play a role in paclitaxel cytotoxicity. We discovered that paclitaxel induces reversible phosphorylation of Bim. Bim initially displays enhanced phosphorylation during paclitaxel-induced mitotic arrest, and then undergoes de-phosphorylation as cells become apoptotic. This dynamic phosphorylation is dependent on mitotic checkpoint signaling. However, while these results suggest that reversible phosphorylation of Bim may contribute to the transmission of a mitotic checkpoint-to-apoptosis signal, we did not observe a strong correlation between Bim protein levels and cellular sensitivity to paclitaxel. Indeed, in contrast to the well-defined role of Bim in paclitaxel-induced cell death in mouse model cells, our depletion studies demonstrate that Bim is not absolutely required for paclitaxel cytotoxicity in breast cancer cell lines. Clearly it is imperative to define the contribution of Bim in paclitaxel-induced apoptosis of clinically relevant targets in order to rationally develop enhanced treatment strategies.
Czernick
Matt
M
Department of Biochemistry, University of Alberta, Edmonton, Alta, Canada.
Rieger
Aja
A
Goping
Ing Swie
IS
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference
D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D003603:Cytotoxins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D017239:Paclitaxel