Xanthohumol inhibits the extracellular signal regulated kinase (ERK) signalling pathway and suppresses cell growth of lung adenocarcinoma cells

Sławińska-Brych, Adrianna; Zdzisińska, Barbara; Dmoszyńska‐Graniczka, Magdalena; Jeleniewicz, Witold; Kurzepa, Jacek; Gagoś, Mariusz; Stepulak, Andrzej

doi:10.1016/j.tox.2016.06.008

Cited by 44 publications

(35 citation statements)

References 47 publications

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“…Activation of ERK1/2 was involved in the anti-tumor resposnes in several other studies in different cancer types including lung [50, 51] although opposite reports have also been reported [52-54]. Thus, the possible dual roles of ERK signaling in terms of tumor suppressor or tumor promoter have been considered depending upon the reagents used, activity of ERK signaling, feedback loops, interaction with other kinase, and cell types studied [46].…”

Section: Discussionmentioning

confidence: 99%

Activation of ERK and Mutual Regulation of Stat3 and SP1 Contribute to Inhibition of PDK1 Expression by Atractylenolide-1 in Human Lung Cancer Cells

Xiao¹,

Zheng²,

Wu³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Atractylodes macrocephula Koidz is an important ingredient in traditional Chinese herbs. One major bioactive compound, atractylenolide-1 (ATL-1), was reported to have anti-inflammatory and anti-tumor activities. However, the underlying molecular mechanism associated to this has not been well elucidated. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Western blot analysis was performed to examine the phosphorylation and protein expression of extracellular signaling-regulated kinase 1/2 (ERK1/2), signal transducer and activator of transcription 3 (Stat3), 3-phosphoinositide dependent protein kinase-1 (PDK1) and transcription factor SP1. QRT-PCR was used to examine the mRNA levels of PDK1 gene. Exogenously expressions of Stat3, PDK1 and SP1 were carried out by transient transfection assays. PDK1 promoter activity was measured by Secrete-Pair Dual Luminescence Assay Kit. A nude mice xenograft model was used to confirm the findings in vitro. Results: We showed that ATL-1 inhibited human lung cancer cell growth and induced cell cycle arrest. Furthermore, we found that ATL-1 stimulated phosphorylation of ERK1/2, inhibited phosphorylation and protein expressions of Stat3 and SP1; the latter were abrogated in the presence of MEK/ERK inhibitor PD98059. Moreover, ATL-1 reduced the protein, mRNA expression and promoter activity of PDK1. Intriguingly, exogenously expressed Stat3 and SP1 overcame ATL-1-inhibited SP1 and Stat3, and PDK1 protein expressions, respectively. Moreover, overexpression of PDK1 resisted the ATL-1-inhibited lung cancer cell growth. In consistent with the results in vitro, ATL-1 inhibited tumor growth, protein expressions of Stat3, SP1 and PDK1, and induced phosphorylation of ERK1/2 in vivo. Conclusion: In summary, our results show that ATL-1 inhibits lung cancer cell growth through activation of ERK1/2, followed by suppressing SP1 protein expression. ATL-1 also reduces phosphorylation and protein levels of Stat3. These are mutual regulation between Stat3 and SP1 proteins affected by ATL-1. This ultimately suppresses PDK1 gene expression. This study reveals a novel mechanism by which ATL-1 inhibits growth of lung cancer cells. Thus, targeting PDK1 pinpoints a potential in the lung cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Activation of ERK and Mutual Regulation of Stat3 and SP1 Contribute to Inhibition of PDK1 Expression by Atractylenolide-1 in Human Lung Cancer Cells

Xiao¹,

Zheng²,

Wu³

et al. 2017

Cell Physiol Biochem

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“…An accumulation of evidence reveals that xanthohumol (XN), a prenylated chalcone extracted from hop plant Humulus lupulus L. (Cannabaceae), has the potential for cancer prevention and therapy [11]. Experimental studies from laboratory and epidemiological investigations and have demonstrated that xanthohumol suppresses a panel of human malignancies, including lung [12], ovarian [13], breast [14], pancreatic [15], prostate [16] and liver [17] cancer. Xanthohumol reportedly processes its anti-tumor effects via inhibition of various signaling pathways, such as disruption of the activation of…”

Section: Introductionmentioning

confidence: 99%

Xanthohumol suppresses glioblastoma via modulation of Hexokinase 2 -mediated glycolysis

et al. 2020

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Deregulation of aerobic glycolysis is a common phenomenon in human cancers, including glioblastoma (GBM). In the present study, we demonstrated that the natural compound xanthohumol has a profound anti-tumor effect on GBM via direct inhibition of glycolysis. Xanthohumol suppressed cell proliferation and colony formation of GBM cells, and significantly impaired glucose metabolism via inhibiting Hexokinase 2 (HK2) expression. We demonstrated that down-regulation of c-Myc was required for xanthohumol-induced decrease of HK2. Xanthohumol destabilization of c-Myc, and promoted FBW7-mediated ubiquitination of c-Myc. Xanthohumol attenuated Akt activity and inhibited the activation of GSK3β, resulted in c-Myc degradation. Overexpression of Myr-Akt1 significantly rescued xanthohumol-mediated c-Myc inhibition and glycolysis suppression. Finally, the xanthohumol-mediated down-regulation of the PI3-K/Akt-GSK3beta-FBW7 signaling axis promoted the destabilization of c-Myc. Finally, the animal results demonstrated that xanthohumol substantially inhibited tumor growth in vivo. Collectively, xanthohumol appears to be a promising new anti-tumor agent with the therapeutic potential for GBM.

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“…Recent studies showed XN increased lipid and glucose metabolism [24][25][26]. Anticarcinogenic properties have been shown on many different cancer cell types including liver, prostate, endometrial, colon, and lung [26][27][28][29][30][31]. The exact mechanism by which XN exerts its effects is not fully understood, however studies suggest that it inhibits cell proliferation and induces apoptosis by upregulating p53, inducing S phase cell cycle control genes, and downregulation of hexokinase II-mediated glycolysis [31][32].…”

Section: Introductionmentioning

confidence: 99%

Hop-derived Xanthohumol Induces HL-60 Leukemia Cells Death

Pacurari

Brown

Rieland

2020

IJBcRR

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Background: Acute promyelocytic leukemia (APL) affects both kids and adults, however it is more prevalent in younger population. Although APL has a favorable prognostic, patients that relapse often do not respond positively to additional chemotherapy. Therefore, there is a need to further identify ways to overcome these challenges. Hypothesis: In this study, we examined antileukemic effects of xanthohumol (XN), a prenylated flavonoid derived from hops (Humulus lupulus L), on human promyelocytic HL-60 cells. Materials and Methods: HL-60 cells were exposed to different concentrations of XN (μM) for 24 h. Cell viability, cell morphology, chromatin condensation, cPARP-1 level, and caspase-3 activation, and the expression of p21 WAF1/Cip1 were analyzed. Results: XN reduced HL-60 cell viability in a dose-dependent manner. XN induced a dosedependent morphological changes including cell shrinkage and blebbing, and significantly increased IJBCRR, 29(1): 61-72, 2020; Article no.IJBCRR.53095 62 the number of cells with condensed chromatin. XN significantly increased the level of cPARP-1, active caspase-3, and the expression of p21WAF/CIP mRNA. Conclusion: These data indicate that XN induces HL-60 cell death by regulating cell cycle progression and apoptosis. This study suggests that XN may have antileukemic preventive effects. Original Research Article

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Xanthohumol inhibits the extracellular signal regulated kinase (ERK) signalling pathway and suppresses cell growth of lung adenocarcinoma cells

Cited by 44 publications

References 47 publications

Activation of ERK and Mutual Regulation of Stat3 and SP1 Contribute to Inhibition of PDK1 Expression by Atractylenolide-1 in Human Lung Cancer Cells

Activation of ERK and Mutual Regulation of Stat3 and SP1 Contribute to Inhibition of PDK1 Expression by Atractylenolide-1 in Human Lung Cancer Cells

Xanthohumol suppresses glioblastoma via modulation of Hexokinase 2 -mediated glycolysis

Hop-derived Xanthohumol Induces HL-60 Leukemia Cells Death

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