Abstract
Paclitaxel is a key member of the Taxane (Taxol/paclitaxel, docetaxel/taxotere) family of successful drugs used in the current treatment of several solid tumors, including ovarian cancer. The molecular target of Taxol/paclitaxel has been identified as tubulin, and paclitaxel binding alters the dynamics and thus stabilizes microtubule bundles. Traditionally, the anti-cancer mechanism of paclitaxel has been thought to originate from its interfering with the role of microtubules in mitosis, resulting in mitotic arrest and subsequent apoptosis. However, recent evidence suggests that paclitaxel operates in cancer therapies via an as-yet-undefined mechanism rather than as a mitotic inhibitor.We found that paclitaxel caused a striking break up of nuclei (referred to as multimicronucleation) in malignant ovarian cancer cells but not in normal cells, and susceptibility to undergo nuclear fragmentation and cell death correlated with a reduction in nuclear lamina proteins, Lamin A/C. Lamin A/C proteins are commonly lost, reduced, or heterogeneously expressed in ovarian cancer, accounting for the aberration of nuclear shape in malignant cells. Mouse ovarian epithelial cells isolated from Lamin A/C null mice were highly sensitive to paclitaxel and underwent nuclear breakage, compared to control wildtype cells. Forced over-expression of Lamin A/C led to resistance to paclitaxel-induced nuclear breakage in cancer cells. Additionally, paclitaxel-induced multimicronucleation occurred independently of cell division that was achieved either by the withdrawal of serum or addition of mitotic inhibitors. These results provide a new understanding for the mitotic-independent mechanism for paclitaxel killing of cancer cells, where paclitaxel induces nuclear breakage in malignant cancer cells that have a malleable nucleus, but not in normal cells that have a stiffer nuclear envelope. As such, we identify that reduced nuclear Lamin A/C protein levels correlate with nuclear shape deformation and is a key determinant of paclitaxel sensitivity of cancer cells.
