Nuclear Lamin A/C Expression Is a Key Determinant of Paclitaxel Sensitivity

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.

The microtubule cytoskeleton: An old validated target for novel therapeutic drugs

“…Do MTD act by targeting dividing cancer cells and the dying cells in turn induce an environmental change leading to the destruction of neighboring cancer cells, a so-called bystander effect, which would allow to target more tumor cells ( Mitchison, 2012 )? Do these drugs perturb other MT functions, especially in interphase ( Wang et al, 1998 ; Giannakakou et al, 2000 ; Stone and Chambers, 2000 ; Ogden et al, 2014 ; Mitchison et al, 2017 ; Smith et al, 2021 )?…”

Elevated levels of lamin A promote HR and NHEJ-mediated repair mechanisms in etoposide-treated ovarian cancer cells

“…Studies have also shown resistance to paclitaxel-induced nuclear breakage in lamin A/C over-expressing cancer cells. It was found that decreased nuclear lamin A/C protein levels correlate with nuclear shape deformation and are a critical predictor of cancer cells’ susceptibility to paclitaxel(95). We have encountered different players of similar processes being significantly affected by the abundance or deficiency of lamin A.…”

Rationale for combination of paclitaxel and CDK4/6 inhibitor in ovarian cancer therapy — non-mitotic mechanisms of paclitaxel

“…This finding provides a new addition to the well-accepted notion that paclitaxel acts as a mitotic inhibitor. Thus, in addition to proliferation, a malleable nuclear envelope caused by a defective nuclear envelope structural proteins ( 69 a) provides another specificity of cancer cells for killing by paclitaxel, as non-neoplastic cells have a sturdier nuclear envelope and are more resistant to paclitaxel-induced breaking ( 59 , 68 ).…”

“…With the realization of the non-mitotic mechanism of paclitaxel in killing cancer cells ( 68 ), a new rationale may motivate the study of adding CDK4/6i to paclitaxel regimen, especially to the dose dense treatment of metastatic breast and recurrent ovarian cancer ( Figure 3 ). Furthermore, ongoing study will yield additional understanding of the potential mechanism(s) of CDK4/6 inhibition in damaging cancer cells, in addition to the cytostatic effects.…”