Cyclin-dependent Kinase-1 (Cdk1)/Cyclin B1 Dictates Cell Fate after Mitotic Arrest via Phosphoregulation of Antiapoptotic Bcl-2 Proteins

Sakurikar, Nandini; Eichhorn, Joshua M.; Chambers, Timothy C.

doi:10.1074/jbc.m112.391854

Cited by 56 publications

(60 citation statements)

References 26 publications

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“…Taxane therapy abrogates completion of mitosis by blocking cells in the G2/M phase of the cell cycle [41, 52-54], and AXL-expressing USC cells accumulate in this phase to a greater degree than AXL-non-expressing cells in the presence of paclitaxel. This G2/M arrest then leads to apoptotic cell death.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Receptor Tyrosine Kinase AXL Restores Paclitaxel Chemosensitivity in Uterine Serous Cancer

Palisoul

Quinn

Schepers

et al. 2017

Molecular Cancer Therapeutics

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Uterine serous cancer (USC) is aggressive, and the majority of recurrent cases are chemoresistant. Because the receptor tyrosine kinase AXL promotes invasion and metastasis of USC and is implicated in chemoresistance in other cancers, we assessed the role of AXL in paclitaxel resistance in USC, determined the mechanism of action, and sought to restore chemosensitivity by inhibiting AXL in vitro and in vivo. We used small hairpin RNAs and BGB324 to knock down and inhibit AXL. We assessed sensitivity of USC cell lines to paclitaxel and measured paclitaxel intracellular accumulation in vitro in the presence or absence of AXL. We also examined the role of the epithelial-mesenchymal transition in AXL-mediated paclitaxel resistance. Finally, we treated USC xenografts with paclitaxel, BGB324, or paclitaxel plus BGB324 and monitored tumor burden. AXL expression was higher in chemoresistant USC patient tumors and cell lines than in chemosensitive tumors and cell lines. Knockdown or inhibition of AXL increased sensitivity of USC cell lines to paclitaxel in vitro and increased cellular accumulation of paclitaxel. AXL promoted chemoresistance even in cells that underwent the epithelial-mesenchymal transition in vitro. Finally, in vivo studies of combination treatment with BGB324 and paclitaxel showed a greater than 51% decrease in tumor volume after 2 weeks of treatment when compared to no treatment or single agent treatments (P<0.001). Our results show that AXL expression mediates chemoresistance independent of EMT and prevents accumulation of paclitaxel. This study supports the continued investigation of AXL as a clinical target, particularly in chemoresistant USC.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the Receptor Tyrosine Kinase AXL Restores Paclitaxel Chemosensitivity in Uterine Serous Cancer

Palisoul

Quinn

Schepers

et al. 2017

Molecular Cancer Therapeutics

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“…In addition, 24:9 phosphorylation of Mcl-1 at Thr92 by Cdk1/cyclin B1 caused its APC-mediated degradation, thus triggering apoptosis during mitotic arrest (Harley et al 2010). Indeed, a mitotic death signature using several cell lines has been identified based on the hypothesis that mitotic cell death occurs as a result of robust Cdk1 signalling where Mcl-1 and Bcl-xL are completely phosphorylated and thereby degraded or inactivated (Sakurikar et al 2012(Sakurikar et al , 2014. Conversely, mitotic slippage was associated with incomplete phosphorylation of Mcl-1 and Bcl-xL.…”

Section: :9mentioning

confidence: 99%

Consequences of mitotic slippage for antimicrotubule drug therapy

Cheng

Crasta

2017

Endocrine-Related Cancer

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Antimicrotubule agents are commonly utilised as front-line therapies against several malignancies, either by themselves or as combination therapies. Cell-based studies have pinpointed the anti-proliferative basis of action to be a consequence of perturbation of microtubule dynamics leading to sustained activation of the spindle assembly checkpoint, prolonged mitotic arrest and mitotic cell death. However, depending on the biological context and cell type, cells may take an alternative route besides mitotic cell death via a process known as mitotic slippage. Here, mitotically arrested cells 'slip' to the next interphase without undergoing proper chromosome segregation and cytokinesis. These post-slippage cells in turn have two main cell fates, either cell death or a G1 arrest ensuing in senescence. In this review, we take a look at the factors determining mitotic cell death vs mitotic slippage, post-slippage cell fates and accompanying features, and their consequences for antimicrotubule drug treatment outcomes.

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“…To explore the molecular mechanisms underlying the effect of Mut TEKT4 on paclitaxel resistance, we focused on the CDK1-cyclin B1 and Bcl-2 signalling pathways, which have been implicated in the G2-M transition of the cell cycle and in paclitaxel-induced apoptosis 23 . Mock, WT and Mut cells were treated with 50 nM paclitaxel for 48 h, and immunoblotting was performed for markers of mitosis (CDK1, cyclin B1), apoptosis (PARP cleavage) and anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-xL and Mcl-1).…”

Section: Tekt4 Variations Were Enriched After Paclitaxel-based Nctmentioning

confidence: 99%

Enriched variations in TEKT4 and breast cancer resistance to paclitaxel

Jiang

Peng

et al. 2014

Nat Commun

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Among chemotherapeutic agents, paclitaxel has shown great efficacy against breast cancer. Prediction of paclitaxel response may improve patient outcomes. Here we show, using exome sequencing, that in comparison with pre-treatment biopsies, two TEKT4 germline variations are enriched in post-treatment tumours. We find TEKT4 variations in B10% of an independent cohort of 84 pairs of samples. Tektin4 (encoded by TEKT4) associates closely with tubulin in doublet microtubules and helps stabilize these structures. These two TEKT4 germline variations in a high cis linkage are biologically relevant, as the ectopic expression of variant TEKT4 deregulates the microtubule stability, antagonizes the paclitaxel-induced stabilizing effect of microtubules and increases paclitaxel resistance. Furthermore, TEKT4 germline variations are associated with reduced disease-free survival and overall survival compared with wild-type TEKT4 in patients undergoing paclitaxel-based chemotherapy. Taken together, we reveal a potential mechanism of resistance to paclitaxel through the acquisition of germline variations in breast cancer.

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Cyclin-dependent Kinase-1 (Cdk1)/Cyclin B1 Dictates Cell Fate after Mitotic Arrest via Phosphoregulation of Antiapoptotic Bcl-2 Proteins

Cited by 56 publications

References 26 publications

Inhibition of the Receptor Tyrosine Kinase AXL Restores Paclitaxel Chemosensitivity in Uterine Serous Cancer

Inhibition of the Receptor Tyrosine Kinase AXL Restores Paclitaxel Chemosensitivity in Uterine Serous Cancer

Consequences of mitotic slippage for antimicrotubule drug therapy

Enriched variations in TEKT4 and breast cancer resistance to paclitaxel

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