Cervical Cancer Growth Is Regulated by a c-ABL–PLK1 Signaling Axis

Xu, Yang; Chen, Gang; Li, Wei; Peng, Changmin; Zhu, Yue; Yang, Xiaoming; Li, Teng; Cao, Cheng; Pei, Huadong

doi:10.1158/0008-5472.can-16-1378

Cited by 40 publications

(29 citation statements)

References 49 publications

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“…In MDA-MB-231 and MDA-MB-468 breast cancer cells, EGFR and ABL kinase inhibitors synergize to prevent in vitro and in vivo growth by inhibiting nuclear translocation of β-catenin and subsequent repression of the long non-coding RNA (lcRNA), HOTAIR, a known tumor promoter [65]. In HeLa cervical cancer cells, ABL1 promotes proliferation, mitotic entry, and xenograft growth by phosphorylating and stabilizing the serine-threonine kinase, polo-like-kinase-1 (PLK1), an essential mitotic regulator [66]. Stable silencing of ABL1 also dramatically blocks proliferation and xenograft growth of glioblastoma cells [67], and in gastric and hepatocellular carcinoma cells, ABL1 is required for proliferation and anchorage-independent growth downstream of MET [68].…”

Section: Abl Kinases Regulate Tumor Growthmentioning

confidence: 99%

“…In colon cancer cells, NOTCH->disabled (DAB)-1 signaling activates ABL1, which phosphorylates the RHO-GEF, TRIO, a pro-invasive modulator of the actin cytoskeleton [57]. Finally, ABL1 also influences microtubule assembly by phosphorylating PLK1, which phosphorylates plus-end microtubule-binding proteins, which regulate cytokinesis [66]. …”

Section: Tumor Progression and Metastasis Driven By Abl Kinasesmentioning

confidence: 99%

“…), reducing interaction with β-TrCP, and increasing β-catenin stability [102]. ABL1 also phosphorylates and stabilizes geminin and PLK-1; although the mechanisms have not yet been defined [71, 66]. …”

Section: Regulation Of Downstream Signalingmentioning

confidence: 99%

“…ABL kinases activate downstream signaling pathways to promote solid tumor proliferation, survival, migration/invasion, and metastasis, and many of these signaling pathways ultimately converge on the induction/activation of transcription factors. These pathways include: STAT3/MMP-1 (melanoma)[69], STAT5/TAZ/IL-6/MMP-1 (breast)[43], TAZ/β-catenin (NSCLC)[102], BRAF/ERK (melanoma)[51], Scar/WAVE/Ena/VASP (breast)[112, 113], cortactin/Arp2/3 (breast) [85], geminin (breast) [70, 71], PLK-1 (cervical) [66], PCNA (breast) [114], SNAIL,TWIST/ZEB1 (breast, melanoma, hepatocellular carcinoma)[80, 90, 84, 91], cathepsin/NME1, (melanoma, breast)[42], SP1/ETS1/NF-κB/cathepsin (melanoma)[40], PKCδ/MMP-2 (hepatocellular carcinoma) [84], p68/β-catenin (prostate, colorectal) [115, 89], and TRIO-RHOA (colon)[57]. Common mechanisms underlying activation of these pathways are described below.…”

Section: Regulation Of Downstream Signalingmentioning

confidence: 99%

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Enabling Tumor Growth and Progression: Recent Progress in Unraveling the Functions of ABL Kinases in Solid Tumor Cells

2018

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Purpose of Review The goal of this review is to summarize our current knowledge regarding how ABL family kinases are activated in solid tumors and impact on solid tumor development/progression, with a focus on recent advances in the field. Recent Findings Although ABL kinases are known drivers of human leukemia, emerging data also implicates the kinases in a large number of solid tumor types where they promote diverse processes such as proliferation, survival, cytoskeletal reorganization, cellular polarity, EMT (epithelial-mesenchymal-transition), metabolic reprogramming, migration, invasion and metastasis via unique signaling pathways. ABL1 and ABL2 appear to have overlapping but also unique roles in driving these processes. In some tumor types, the kinases may act to integrate pro- and anti-proliferative and -invasive signals, and also may serve as a switch during EMT/MET (mesenchymal-epithelial) transitions. Conclusions Most data indicate that targeting ABL kinases may be effective for reducing tumor growth and preventing metastasis; however, ABL kinases also may have a tumor suppressive role in some tumor types and in some cellular contexts. Understanding the functions of ABL kinases in solid tumors is critical for developing successful clinical trials aimed at targeting ABL kinases for the treatment of solid tumors.

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Section: Abl Kinases Regulate Tumor Growthmentioning

confidence: 99%

Section: Tumor Progression and Metastasis Driven By Abl Kinasesmentioning

confidence: 99%

Section: Regulation Of Downstream Signalingmentioning

confidence: 99%

Section: Regulation Of Downstream Signalingmentioning

confidence: 99%

See 2 more Smart Citations

Enabling Tumor Growth and Progression: Recent Progress in Unraveling the Functions of ABL Kinases in Solid Tumor Cells

2018

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“…ABL1 kinase controls cell growth, survival and invasion . In Ph‐positive leukemia cell lines, the expression levels of ABL1 were more than 50‐fold lower compared with that of the BCR‐ABL fusion gene (data not shown); however, promotion of cancer growth by ABL1 has been reported in solid tumors . AIC‐47 might be effective in ABL1‐activated solid tumors.…”

Section: Discussionmentioning

confidence: 99%

Potent antiproliferative effect of fatty‐acid derivative AIC‐47 on leukemic mice harboring BCR‐ABL mutation

et al. 2019

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Therapy based on targeted inhibition of BCR‐ABL tyrosine kinase has greatly improved the prognosis for patients with Philadelphia chromosome (Ph)‐positive leukemia and tyrosine kinase inhibitors (TKI) have become standard therapy. However, some patients acquire resistance to TKI that is frequently associated with point mutations in BCR‐ABL. We previously reported that a medium‐chain fatty‐acid derivative AIC‐47 induced transcriptional suppression of BCR‐ABL and perturbation of the Warburg effect, leading to growth inhibition in Ph‐positive leukemia cells. Herein, we showed that AIC‐47 had anti‐leukemic effects in either wild type (WT)‐ or mutated‐BCR‐ABL‐harboring cells. AIC‐47 suppressed transcription of BCR‐ABL gene regardless of the mutation through downregulation of transcriptional activator, c‐Myc. Reprogramming of the metabolic pathway has been reported to be associated with resistance to anti‐cancer drugs; however, we found that a point mutation of BCR‐ABL was independent of the profile of pyruvate kinase muscle (PKM) isoform expression. Even in T315I‐mutated cells, AIC‐47 induced switching of the expression profile of PKM isoforms from PKM2 to PKM1, suggesting that AIC‐47 disrupted the Warburg effect. In a leukemic mouse model, AIC‐47 greatly suppressed the increase in BCR‐ABL mRNA level and improved hepatosplenomegaly regardless of the BCR‐ABL mutation. Notably, the improvement of splenomegaly by AIC‐47 was remarkable and might be equal to or greater than that of TKI. These findings suggest that AIC‐47 might be a promising agent for overcoming the resistance of Ph‐positive leukemia to therapy.

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A Redox‐Triggered Bispecific Supramolecular Nanomedicine Based on Peptide Self‐Assembly for High‐Efficacy and Low‐Toxic Cancer Therapy

Yang

Zhou

et al. 2019

Adv Funct Materials

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Polo‐like kinase 1 (PLK1) and polo‐like kinase 4 (PLK4) are closely associated with the progression of several cancers, and their bispecific inhibitors can kill tumor cells effectively. Herein, a redox‐responsive bispecific supramolecular nanomedicine based on the self‐assembly of a cyclic peptide, termed as C‐1, targeting both PLK1 and PLK4 as a potent anticancer agent is reported. C‐1 is a cyclic peptide in response to reducing agents such as glutathione (GSH), which is constructed by a combined approach of pharmacophore modeling, molecular docking, and reversible cyclization. After entering the cytosol of cancer cell, the disulfide linkage is reduced by intracellular GSH, with the resulting linear conformation self‐assembling into bispecific nanofibers. C‐1 can lead to apoptotic cell death by inducing caspase‐3 activation and PARP cleavage in HeLa cells. Moreover, it suppresses the growth of HeLa cells in cell assays, and inhibits the progression of HeLa cells‐induced xenografts in nude mice without inducing notable side effects. This work provides a successful example of developing the redox‐responsive bispecific nanomedicine for high‐efficacy and low‐toxic cancer therapy.

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Cervical Cancer Growth Is Regulated by a c-ABL–PLK1 Signaling Axis

Cited by 40 publications

References 49 publications

Enabling Tumor Growth and Progression: Recent Progress in Unraveling the Functions of ABL Kinases in Solid Tumor Cells

Enabling Tumor Growth and Progression: Recent Progress in Unraveling the Functions of ABL Kinases in Solid Tumor Cells

Potent antiproliferative effect of fatty‐acid derivative AIC‐47 on leukemic mice harboring BCR‐ABL mutation

A Redox‐Triggered Bispecific Supramolecular Nanomedicine Based on Peptide Self‐Assembly for High‐Efficacy and Low‐Toxic Cancer Therapy

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