Displacement of Bim by Bmf and Puma rather than increase in Bim level mediates paclitaxel-induced apoptosis in breast cancer cells

Abstract

Taxanes exert their antitumor effect via stabilizing microtubule dynamics and initiating G2/M arrest in cancer cells followed by apoptotic cell death. However, the signaling pathways that connect paclitaxel-induced microtubule perturbation to mitochondrial outer membrane permeabilization (MOMP) and cytochrome c release are not well characterized. Here we demonstrate that in breast cancer cells paclitaxel induces a novel displacement mechanism: prodeath BH3-only proteins Bmf and Puma competitively displace prodeath BH3-only protein Bim from anti-apoptotic proteins to activate Bax and Bak and commit the cell to apoptotic death. Bim and either Puma or Bmf are required for paclitaxel toxicity. While prior mechanisms of apoptosis induced by taxol have focused on changes in Bim levels, we find that an increase is not required for paclitaxel killing of breast cancer cells. Rather, competitive displacement of Bim from anti-apoptotic proteins is the key step committing the cell to death. This novel mechanism suggests the potential utility of novel therapies targeted at altering BH3-only protein heterodimerization.

Restraining FOXO3-dependent transcriptional BMF activation underpins tumour growth and metastasis of E-cadherin-negative breast cancer

“…42,43 Recent studies indicated that BH3-mimetics can be used to treat nonlymphoid cancers but mostly in combination with oestrogen antagonists, proteasome inhibitors, specific PI3K-mTOR inhibitors or chemotherapy. 24,[44][45][46][47][48][49] As previous findings from our laboratory demonstrated that E-cadherin-negative lobular breast cancer depends on p120-catenin-mediated activation of RhoA, Rock and subsequent actomyosin contraction, 26 we anticipate that dual inhibition of these pathways might be successful in E-cadherin-negative cancers that are not driven by oncogenic activation of GFR pathways. Although we do not yet know whether RhoA-Rock signals converge onto the GFR-AKT-FOXO axis in the regulation of anoikis resistance, the fact that FOXO expression had no effect on survival of B-RAF/KRAS-mutated MDA-MB-231 cells seems to be in line with this assumption.…”

Cyclin B1 interacts with the BH3-only protein Bim and mediates its phosphorylation by Cdk1 during mitosis

“…For example, paclitaxel treatment of breast cancer cells results in either a Bmf-or Puma-mediated displacement of Bim from either Bcl-2 or Bcl-X L complexes allowing Bim to bind Bak or Bax and initiate cell death. 16 Furthermore, the transient siRNA knockdown of Bim reduces the susceptibility of prostate and breast cancer cells to Taxol-mediated cell death 17,18 and Bim -/-B and T cells are resistant to cell death induced by Taxol. 19 Collectively, these studies highlight an essential role for Bim during Taxol mediated death of tumor cells; however, to date the precise action of Bim following Taxol treatment remains unknown.…”

Apoptotic-like death occurs through a caspase-independent route in colon carcinoma cells undergoing mitotic catastrophe

“…Although the relation between the spindle checkpoint and cell death remains obscure, it has been suggested that BUB1 mediation of caspaseindependent mitotic death determines cell fate [40]. Furthermore, the perturbation of microtubule dynamics induces BIM translocation from microtubule to mitochondria, where it could exert its pro-apoptotic activity [41]. The absence of significant changes in the mitochondrial membrane potential after treatment with 95 nM PTX (Fig.…”