Involvement of Ras/Raf‐1/ERK actions in the magnolol‐induced upregulation of p21 and cell‐cycle arrest in colon cancer cells

Hsu, Yi Fan; Lee, Tong Sheng; Lin, Shyr Yi; Hsu, Sung Po; Juan, Shu Hui; Hsu, Yuan Nian; Wen, Zhenhua; Lee, Wen Sen

doi:10.1002/mc.20274

Cited by 42 publications

(37 citation statements)

References 25 publications

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“…10 It is of interest that up-regulation of p21 CIP1/WAF1 mRNA but down-regulation of its protein after Fe depletion are different to the effects on its expression during cell-cycle arrest in response to other conditions. For instance, previous studies showed that p21 CIP1/WAF1 mRNA and protein were up-regulated during cellcycle arrest, [74][75][76][77] suggesting increased expression at the transcriptional and posttranscriptional levels. Moreover, in the current study, G 1 /S arrest induced by FCS starvation caused downregulation of both p21 CIP1/WAF1 mRNA and protein levels in MCF-7 cells (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Iron chelation and regulation of the cell cycle: 2 mechanisms of posttranscriptional regulation of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1 by iron depletion

Richardson

2007

Blood

123

103

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Iron (Fe) plays a critical role in proliferation, and Fe deficiency results in G 1 /S arrest and apoptosis. However, the precise role of Fe in cell-cycle control remains unclear. We observed that Fe depletion increased the mRNA of the universal cyclindependent kinase inhibitor, p21 CIP1/WAF1 , while its protein level was not elevated. This observation is unique to the G 1 /S arrest seen after Fe deprivation, as increased p21 CIP1/WAF1 mRNA and protein are usually found when arrest is induced by other stimuli. In this study, we examined the posttranscriptional regulation of p21 CIP1/WAF1 after Fe depletion and demonstrated that its down-regulation was due to 2 mechanisms: (1) inhibited translocation of p21 CIP1/WAF1 mRNA from the nucleus to cytosolic translational machinery; and (2) induction of ubiquitin-independent proteasomal degradation. Iron chelation significantly (P < .01) decreased p21 CIP1/WAF1 protein half-life from 61 (؎ 4 minutes; n ‫؍‬ 3) to 28 (؎ 9 minutes, n ‫؍‬ 3). Proteasomal inhibitors rescued the chelatormediated decrease in p21 CIP1/WAF1 protein, while lysosomotropic agents were not effective. In Fe-replete cells, p21 CIP1/WAF1 was degraded in an ubiquitin-dependent manner, while after Fe depletion, ubiquitinindependent proteasomal degradation occurred. These results are important for considering the mechanism of Fe depletion-mediated cell-cycle arrest and apoptosis and the efficacy of chelators as antitumor agents. IntroductionIron (Fe) is critical for many processes, such as DNA synthesis and energy production. 1,2 Tumor cells require more Fe for DNA synthesis than normal cells, which is probably related to their rapid proliferation. 3,4 This is supported by the fact that tumor cells, compared with their normal counterparts, have significantly higher expression of transferrin receptor 1 (TfR1), a molecule involved in Fe uptake from the transferrin. 3 Many studies have demonstrated that Fe chelators have inhibitory effects on growth of tumor cells. 2,5 Chelators, such as desferrioxamine (DFO), show effective anticancer activity. [6][7][8] However, use of DFO is limited by its poor membrane permeability and short half-life. 9 Currently, Fe chelators that show much greater antiproliferative activity than DFO are in development and include thiosemicarbazones 5,10-13 and tachpyridine. 14,15 There are multiple mechanisms involved in the antitumor activity of Fe chelators. 9,15 Fe depletion results in inhibition of the Fe-containing enzyme, ribonucleotide reductase, which is critical for DNA synthesis. 9 Treatment of cells with Fe chelators downregulates Bcl-2 levels, up-regulates the proapoptotic protein Bax, and significantly increases caspase-3, caspase-8, and caspase-9. 11,16 Consequently, these concerted effects induce apoptosis. 11 Previous studies demonstrated that Fe depletion also alters expression of many molecules that cause cell-cycle arrest. 9,[17][18][19][20][21][22][23][24][25][26] Cyclins and cyclin-dependent kinases (cdks) form active cyclincdk complexes to phosphorylate the re...

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Section: Discussionmentioning

confidence: 99%

Iron chelation and regulation of the cell cycle: 2 mechanisms of posttranscriptional regulation of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1 by iron depletion

Richardson

2007

Blood

123

103

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“…Cells were transfected with 100 nM of CDKN1A (p21), NF-kB (p50 or 65) siRNA or non-specific siRNA (Bioneer, Co., Daejon, Korea) and p21 mutant plasmid (CDKN1A p21, obtained from Dr Anindya Dutta, Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA), which has mutated cyclin D1/CDK4 complex binding site (Cy1 site, ᭝17-24) using WelFect-EX plus transfection reagent (WelGENE, Seoul, Korea) prepared in a serum-free culture medium at 37°C (Hsu et al, 2007). After 6 h, a complete medium was added and the cells were further cultured for 24 h.…”

Section: Transfection Of Sirna and P21 Mutant Plasmidmentioning

confidence: 99%

4‐O‐methylhonokiol, a PPARγ agonist, inhibits prostate tumour growth: p21‐mediated suppression of NF‐κB activity

Lee

Ban

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSEThe effects of 4-O-methylhonokiol (MH), a constituent of Magnolia officinalis, were investigated on human prostate cancer cells and its mechanism of action elucidated. EXPERIMENTAL APPROACHThe anti-cancer effects of MH were examined in prostate cancer and normal cells. The effects were validated in vivo using a mouse xenograft model. KEY RESULTSMH increased the expression of PPARg in prostate PC-3 and LNCap cells. The pull-down assay and molecular docking study indicated that MH directly binds to PPARg. MH also increased transcriptional activity of PPARg but decreased NF-kB activity. MH inhibited the growth of human prostate cancer cells, an effect attenuated by the PPARg antagonist GW9662. MH induced apoptotic cell death and this was related to G0-G1 phase cell cycle arrest. MH increased the expression of the cell cycle regulator p21, and apoptotic proteins, whereas it decreased phosphorylation of Rb and anti-apoptotic proteins. Transfection of PC3 cells with p21 siRNA or a p21 mutant plasmid on the cyclin D1/ cycline-dependent kinase 4 binding site abolished the effects of MH on cell growth, cell viability and related protein expression. In the animal studies, MH inhibited tumour growth, NF-kB activity and expression of anti-apoptotic proteins, whereas it increased the transcriptional activity and expression of PPARg, and the expression of apoptotic proteins and p21 in tumour tissues. CONCLUSIONS AND IMPLICATIONMH inhibits growth of human prostate cancer cells through activation of PPARg, suppression of NF-kB and arrest of the cell cycle. Thus, MH might be a useful tool for treatment of prostate cancer. AbbreviationCDK, cycline-dependent kinase; CNBr, cyanogen bromide; DAPI, 4',6-diamidino-2-phenylindole; GSK-3 b, glycogen synthase kinase 3 b; IAP1, inhibitor of apoptosis 1; iNOS, inducible NOS; MH, 4-O-methylhonokiol

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“…18,19) Several researchers have shown that magnolol inhibits proliferation and induces apoptosis in cancer cells by upregulating p21 cip/Waf1 , 20) inhibiting DNA synthesis, 21) activating the epidermal growth factor receptor (EGFR)/phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, 18) as well as Ras/Raf-1/ Erk actions. 22) However, it remains to be determined whether Note * To whom correspondence should be addressed. e-mail: jykim@cnu.ac.kr…”

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confidence: 99%

Magnolol-Induced Apoptosis in HCT-116 Colon Cancer Cells Is Associated with the AMP-Activated Protein Kinase Signaling Pathway

Park

Lee

Young

et al. 2012

Biological & Pharmaceutical Bulletin

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Colon cancer is the third most common malignancy around the world. Surgery, chemotherapy, and radiotherapy are generally used to treat colon cancer, but no effective therapy for advanced colon carcinoma is available. Therefore, there is a need to identify other therapeutic agents against this disease. Magnolol, a hydroxylated biphenyl compound present in Magnolia officinalis, exerts anticancer potential and low toxicity. Emerging evidence has suggested that activation of AMP-activated protein kinase (AMPK), a potential cancer therapeutic target is involved in apoptosis in colon cancer cells. However, the effects of magnolol on human colon cancer through activation of AMPK remain unexplored. In this study, we explored whether magnolol exerts an antiproliferative effect, and induces apoptosis in HCT-116 human colon cancer cells.

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Involvement of Ras/Raf‐1/ERK actions in the magnolol‐induced upregulation of p21 and cell‐cycle arrest in colon cancer cells

Cited by 42 publications

References 25 publications

Iron chelation and regulation of the cell cycle: 2 mechanisms of posttranscriptional regulation of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1 by iron depletion

Iron chelation and regulation of the cell cycle: 2 mechanisms of posttranscriptional regulation of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1 by iron depletion

4‐O‐methylhonokiol, a PPARγ agonist, inhibits prostate tumour growth: p21‐mediated suppression of NF‐κB activity

Magnolol-Induced Apoptosis in HCT-116 Colon Cancer Cells Is Associated with the AMP-Activated Protein Kinase Signaling Pathway

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