RanBP1 downregulation sensitizes cancer cells to taxol in a caspase-3-dependent manner

Abstract

Mitotic microtubule (MT)-targeting drugs are widely used to treat cancer. The GTPase Ran regulates multiple processes, including mitotic spindle assembly, spindle pole formation and MT dynamics; Ran activity is therefore essential to formation of a functional mitotic apparatus. The RanBP1 protein, which binds Ran and regulates its interaction with effectors, is overexpressed in many cancer types. Several observations indicate that RanBP1 contributes to regulate the function of the mitotic apparatus: RanBP1 inactivation yields hyperstable MTs and induces apoptosis during mitosis, reminiscent of the effects of the MT-stabilizing drug taxol. Here we have investigated the influence of RanBP1 on spontaneous and taxol-induced apoptosis in transformed cells. We report that RanBP1 downregulation by RNA interference activates apoptosis in several transformed cell lines regardless of their p53 status, but not in the caspase-3-defective MCF-7 breast cancer cell line. Furthermore, RanBP1-interfered cells show an increased apoptotic response to taxol compared to their counterpart with normal or high RanBP1 levels, and this response is caspase-3 dependent. These results indicate that RanBP1 can modulate the outcome of MT-targeting therapeutic protocols.

The Regulations of Deubiquitinase USP15 and Its Pathophysiological Mechanisms in Diseases

“…A variety of cell death phenomena have been associated with paclitaxel, ranging from interrupting microtubule dynamics to cell cycle arrest at the G2/M phase and promoting the serial cleavage events of apoptotic effector caspases (CASPs), such as caspase-10, -8, -7, and -3 [68,69,70]. A report suggested that paclitaxel sensitivity has a positive correlation with USP15 protein expression in HeLa cells, and that the binding of procaspase-3 with the components of SCF (Skp1-CUL1-F-box) may be controlled by USP15.…”

Ran control of mitosis in human cells: gradients and local signals

“…The finding that RanBP1 abundance is critical for mitotic MT function opens a new issue, raising the possibility that it may influence the efficacy of MT-targeting chemotherapeutic drugs when deregulated in cancer cells. Indeed, RanBP1 silencing increased the sensitivity of transformed cells to taxol [47]; retrospectively, this can account for the observed paclitaxel resistance in RanBP1-overexpressing breast cancers (http://www.ncbi.nlm.nih.gov/geo; see RanBP1 in dataset record GDS360). Therefore, in a newly emerging scenario, RanGTP activity can amplify or antagonize the effect, and hence the therapeutic outcome, of MT-targeting drugs in cancer cells.…”

Mitotic cell death induction by targeting the mitotic spindle with tubulin-inhibitory indole derivative molecules

“…First, the expression profile of genes encoding MT-associated and MT-regulatory proteins found in different cancer types, and also within cells from a same cancer, can synergize with, or antagonize, the effect of the drugs [12–14]. Second, tumor cells can develop resistance through diverse mechanisms [4, 15–17], involving not only the induction of efflux pump mechanisms implicated in multidrug resistance, but also the presence of mutations or differential expression of tubulin isotypes [18–21].…”