Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA.
Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida, USA.
Mol Cell Biol. 2021 Jun 23;41(7):e0064820. doi: 10.1128/MCB.00648-20.
Paclitaxel is a key member of the Taxane (paclitaxel [originally named taxol], docetaxel/Taxotere) family of successful drugs used in the current treatment of several solid tumors, including ovarian cancer. The molecular target of paclitaxel has been identified as tubulin, and paclitaxel binding alters the dynamics and thus stabilizes microtubule bundles. Traditionally, the anticancer 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 wild-type cells. Forced overexpression 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 by either the withdrawal of serum or the addition of mitotic inhibitors. These results provide a new understanding for the mitotis-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 are a key determinant of paclitaxel sensitivity of cancer cells.
紫杉醇是紫杉烷（紫杉醇[原名紫杉醇]、多西紫杉醇/泰素）类成功药物中的关键成员，用于治疗多种实体肿瘤，包括卵巢癌。紫杉醇的分子靶标已被确定为微管蛋白，紫杉醇结合改变了微管的动力学，从而稳定微管束。传统上，紫杉醇的抗癌机制被认为源于其干扰微管在有丝分裂中的作用，导致有丝分裂停滞和随后的细胞凋亡。然而，最近的证据表明，紫杉醇在癌症治疗中的作用机制尚不清楚，而不是作为有丝分裂抑制剂。我们发现紫杉醇在恶性卵巢癌细胞中引起细胞核明显破裂（称为多核化），但在正常细胞中则不会，并且易发生核碎裂和细胞死亡与核层蛋白 lamin A/C 的减少相关。Lamin A/C 蛋白在卵巢癌中通常丢失、减少或表达异质性，导致恶性细胞的核形状异常。从 lamin A/C 缺失的小鼠中分离的小鼠卵巢上皮细胞对紫杉醇高度敏感，并发生核破裂，而对照野生型细胞则没有。lamin A/C 的强制过表达导致癌细胞对紫杉醇诱导的核破裂产生抗性。此外，紫杉醇诱导的多核化发生在细胞分裂之外，通过血清去除或有丝分裂抑制剂的添加来实现。这些结果为紫杉醇杀死癌细胞的有丝分裂非依赖性机制提供了新的认识，其中紫杉醇诱导恶性癌细胞的核破裂，而正常细胞的核膜较硬则不会发生核破裂。因此，我们确定核 lamin A/C 蛋白水平的降低与核形状变形相关，并且是癌细胞对紫杉醇敏感性的关键决定因素。
