Aurora Kinase Inhibition Induces PUMA via NF-κB to Kill Colon Cancer Cells

Sun, Jing; Knickelbein, Kyle; He, Kan; Chen, Dongshi; Dudgeon, Crissy; Shu, Yongqian; Yu, Jian; Zhang, Lin

doi:10.1158/1535-7163.mct-13-0846

Cited by 33 publications

(39 citation statements)

References 38 publications

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“…Previous studies have shown that NF‐κB pathway and p73 were involved in PUMA activation . However, the phosphorylation level of p65 and the expression of p73 remained unchanged after VB1 treatment.…”

Section: Discussionmentioning

confidence: 85%

“…It can be transcriptionally activated by p53 in response to DNA‐damaging agents . The activation of PUMA by nongenotoxic stimuli is p53‐independent and mediated by different transcription factors, including p53 homologue p73, forkhead box O3a (FoxO3a), and nuclear factor‐kappa B (NF‐κB) . Upon induction, PUMA facilitates mitochondrial outer membrane permeabilization and caspase activation cascade to regulate Bcl‐2‐associated X protein (Bax) activity .…”

Section: Introductionmentioning

confidence: 99%

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Purified vitexin compound 1, a new neolignan isolated compound, promotes PUMA‐dependent apoptosis in colorectal cancer

et al. 2018

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Purified vitexin compound 1 (VB1, a neolignan isolated and extracted from the seed of Chinese herb Vitex negundo) is an effective antitumor agent and exhibits promising clinical activity against various cancers including colorectal cancer. However, it remains unknown about the precise underlying mechanism associated with the antitumor effect of VB1 and how it triggers apoptosis in cancer cells. Here, we demonstrated that VB1 promoted apoptosis via p53‐dependent induction of p53 upregulated modulator of apoptosis (PUMA) and further to induce Bax (Bcl‐2‐associated X protein) activation and mitochondrial dysfunction in colon cancer HCT‐116 and LoVo cells. Deficiency in p53, PUMA, or Bax abrogated VB1‐induced apoptosis and promoted cell survival in HCT‐116 cells. Furthermore, the combination of VB1 with chemotherapeutic drugs 5‐fluorouracil (5‐FU) or NVP‐BZE235 resulted in a synergistic antitumor effect via PUMA induction in HCT‐116 cells. VB1 significantly suppressed the cell proliferation of wild‐type (WT) HCT‐116 and LoVo cells in vitro and tumor growth in vivo. The results indicate that p53/PUMA/Bax axis plays a critical role in VB1‐induced apoptosis and VB1 may have valuable clinical applications in cancer therapy as a novel anticancer agent used alone or in combination with other chemotherapeutic drugs.

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Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Purified vitexin compound 1, a new neolignan isolated compound, promotes PUMA‐dependent apoptosis in colorectal cancer

et al. 2018

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“…Wang et al has recently reported that PUMA is a direct target of NF-κB and mediates TNF-α-induced apoptosis in vitro and in vivo [24]. Sun et al has also reported that PUMA was directly activated by p65 through the canonical NF-κB pathway, mediating the apoptotic response to mitotic arrest imposed by aurora kinase inhibition [25]. Dynamic changes in lncRNA expression have been demonstrated upon activation of NF-kB signalling.…”

Section: Discussionmentioning

confidence: 99%

Targeting MIAT reduces apoptosis of cardiomyocytes after ischemia/reperfusion injury

Chen¹,

Zhang²,

Yu³

et al. 2019

Bioengineered

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This study aims to investigate the role of targeting lncRNA myocardial infarction-associated transcript (MIAT) in protection against hypoxia/reoxygenation (H/R) injury in H9c2 cells in vitro and myocardial ischemia/reperfusion (I/R) injury in vivo by regulating expression of NF-kB and p53 upregulated modulator of apoptosis (PUMA). H9C2 cells were infected with lentivirus expressing the short-hairpin RNA direct against human MIAT gene (Lv-MIAT shRNA) or lentivirus expressing scrambled control (Lv-NC shRNA) or PUMA siRNA or p65 siRNA or their control siRNA respectively. Then the H9c2 cells were infected with Lv-shRNA to 2 hours of hypoxia (H) and 24 hour of reoxygenation (R). 100 ul of Lv-MIAT shRNA (1 × 10 8 PFU) or Lv-NC shRNA was transfected into mouse hearts, then the hearts were subjected to I/R (1h/72 h). We discovered targeting MIAT remarkably enhanced H9c2 cell viability, decreased H/R-induced cell apoptosis and LDH leakage and significantly decreased I/R-induced myocardial infarct size, reduced myocardial apoptosis and enhanced the heart function. Targeting MIAT downregulated p65 nuclear translocation, NF-κB activity and anti-apoptotic protein cleaved-caspase-3, Bax, and upregulated anti-apoptotic protein Bcl-2 induced by H/R or I/R. Our study suggests that targeting MIAT may protect against H9c2 cardiomyoblasts H/R injury or myocardial I/R injury via inhibition of cell apoptosis, mediated by NF-κB and PUMA signal pathway. ARTICLE HISTORY

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“…Our laboratory discovered that inhibition of Aurora‐A increases the Bax/Bcl‐2 expression ratio, a favorable pro‐apoptotic predictor for drug response in AML . The expression of PUMA, another modulator of apoptosis, is significantly increased after suppression of Aurora‐A by siRNA or small‐molecule inhibitors . Inhibition of Aurora‐A also induces expression of the pro‐apoptotic protein Bim and triggers apoptosis in AML cells.…”

Section: Functions Of Aurora‐amentioning

confidence: 99%

“…62 The expression of PUMA, another modulator of apoptosis, is significantly increased after suppression of Aurora-A by siRNA or small-molecule inhibitors. 63 Inhibition of Aurora-A also induces expression of the pro-apoptotic protein Bim and triggers apoptosis in AML cells. Accordingly, pro-apoptotic signals are downregulated by Aurora-A through the phosphorylation and degradation of BimEL, the major splice variant of Bim.…”

Section: Anti-apoptosismentioning

confidence: 99%

Aurora‐A Kinase: A Potent Oncogene and Target for Cancer Therapy

Yan

Wang

et al. 2016

Medicinal Research Reviews

217

181

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The Aurora kinase family comprises three serine/threonine kinases, Aurora-A, -B and -C. Among these, Aurora-A and -B play central roles in mitosis, whereas Aurora-C executes unique roles in meiosis. Overexpression or gene amplification of Aurora kinases have been reported in a broad range of human malignancies, pointing to their role as potent oncogenes in tumorigenesis.Aurora kinases therefore represent promising targets for anticancer therapeutics. So far, a number of Aurora kinase inhibitors (AKIs) have been generated, of which some are currently undergoing clinical trials. Recent studies have unveiled novel unexpected functions of Aurora kinases during cancer development and the mechanisms underlying the anticancer actions of AKIs. In this review, we discuss the most recent advances in Aurora-A kinase research and targeted cancer therapy, focusing on the oncogenic roles and signaling pathways of Aurora-A kinases in contributing tumorigenesis, the recent preclinical and clinical AKI data and potential alternative routes for Aurora-A kinase inhibition.Key words: Aurora-A; Aurora kinase inhibitors (AKIs); targeted cancer therapy; mitosis; tumorigenesis 3 In mammals, the Aurora family of serine/threonine kinases consists of Aurora-A, -B and -C, which share a highly conserved catalytic domain containing auto-phosphorylating sites. The catalytic domain is flanked by a very short C-terminal tail and an N-terminal domain of variable lengths 1,2 . In the C-terminal regions of Auroras, there exists a short amino-acid peptide motif called "destruction box" (D-box). The D-box is recognized by the anaphase-promoting complex/cyclosome (APC/C) for degradation through the ubiquitin/proteasome-dependent pathway ( Fig. 1A). Despite their structural similarities, the expression patterns, cellular localization and physiological functions of these three Aurora kinases are largely distinct.Aurora-A and -B are commonly expressed in most cell types whereas Aurora-C is specially expressed in the testis. Both Aurora-A and -B play key roles in regulating cell-cycle progression from G2 through to cytokinesis. Aurora-C has a unique physiological role in spermatogenesis and functions as a chromosomal passenger protein similar to Aurora-B in mitosis 2 .Overexpression of Aurora-A and -B have been found in multiple types of cancer (Table 1), which function as oncogenes to promote tumorigenesis, providing potential targets for cancer therapy.However, comparatively little information is available regarding the roles of Aurora-C in cancer.In this review, we will focus on recent progress as well as the main unresolved issues associated with Aurora-A in cancer.4 1 FUNCTIONS OF AURORA-A In normal cells a. MitosisIn G1 phase, the level of Aurora-A is rarely detectable. During S phase, a small proportion of Aurora-A is first detected at centrosomes. At late G2 phase, Aurora-A accumulates evidently at centrosomes and becomes activated 3 . During prometaphase and metaphase, active Aurora-A localizes on bipolar spindles and spindle poles after...

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Aurora Kinase Inhibition Induces PUMA via NF-κB to Kill Colon Cancer Cells

Cited by 33 publications

References 38 publications

Purified vitexin compound 1, a new neolignan isolated compound, promotes PUMA‐dependent apoptosis in colorectal cancer

Purified vitexin compound 1, a new neolignan isolated compound, promotes PUMA‐dependent apoptosis in colorectal cancer

Targeting MIAT reduces apoptosis of cardiomyocytes after ischemia/reperfusion injury

Aurora‐A Kinase: A Potent Oncogene and Target for Cancer Therapy

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