Unbalanced activation of ERK1/2 and MEK1/2 in apigenin-induced HeLa cell death

Llorens, Franc; Miró, Francesc; Casañas, Arnau; Roher, Nerea; Garcia, Lourdes; Plana, Maria; Gómez, Néstor; Itarte, Emilio

doi:10.1016/j.yexcr.2004.05.006

Cited by 31 publications

(26 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3B shows that apigenin partially inhibits activation in response to constitutively active Ras (caRas) and nearly completely inhibits MEKK1-dependent promoter activation. This is consistent with findings in HeLa cells that apigenin can antagonize Ras action (55). As shown in Fig.…”

Section: Apigenin Suppresses Involucrin Gene Expression-involucrinsupporting

confidence: 93%

Apigenin Inhibition of Involucrin Gene Expression Is Associated with a Specific Reduction in Phosphorylation of Protein Kinase Cδ Tyr311

Balasubramanian

Zhu

Eckert

2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Apigenin is a plant-derived flavanoid that has significant promise as a skin cancer chemopreventive agent. In the present study, we examine the mechanism whereby apigenin regulates normal human keratinocyte differentiation. Expression of involucrin (hINV), a marker of keratinocyte differentiation, is increased by differentiating agents via a protein kinase C␦ (PKC␦), Ras, MEKK1, MEK3 cascade that increases AP1 factor level and AP1 factor binding to DNA elements in the hINV promoter. We show that apigenin inhibits this response. Apigenin suppresses the 12-O-tetradeconylphorbol-13-acetate-dependent increase in AP1 factor expression and binding to the hINV promoter and the increase in hINV promoter activity. Apigenin also inhibits the increase in promoter activity observed following overexpression of PKC␦, constitutively active Ras, or MEKK1. The suppression of PKC␦ activity is associated with reduced phosphorylation of PKC␦-Y311. The physiological importance of this phosphorylation event was confirmed by showing that the PKC␦ phosphorylation-defective mutant, PKC␦-Y311F, is less able to increase hINV promoter activity. Activation of hINV promoter activity by the green tea polyphenol, (؊)-epigellocathecin-3-gallate, is also inhibited by apigenin, suggesting that the two chemopreventive agents can produce opposing actions in keratinocytes. Additional studies show that the apigenin-dependent suppression of differentiation is associated with reduced cell proliferation but that there is no evidence of apoptosis.

show abstract

Section: Apigenin Suppresses Involucrin Gene Expression-involucrinsupporting

confidence: 93%

Apigenin Inhibition of Involucrin Gene Expression Is Associated with a Specific Reduction in Phosphorylation of Protein Kinase Cδ Tyr311

Balasubramanian

Zhu

Eckert

2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Our previous studies using specific inhibitors of MEK1/2 and p38 demonstrated an inhibition of PC-3 cell proliferation in parallel with inhibition of phosphorylation of ERK1/2 and p38 (19). Interestingly, high phosphorylation of ERK1/2 was observed after treatment of cells with apigenin which usually do not activate the downstream signaling molecules that favors cell proliferation (31). Akt is another major influence in IGF-I signaling, and a number of factors regulated by Akt have been shown to be involved in regulating cell survival and proliferation (32).…”

Section: Discussionmentioning

confidence: 99%

Apigenin Attenuates Insulin-Like Growth Factor-I Signaling in an Autochthonous Mouse Prostate Cancer Model

Shukla

MacLennan

et al. 2011

Pharm Res

View full text Add to dashboard Cite

Purpose Deregulation of IGF signaling plays an important role in prostate cancer and contributes to invasion and metastasis. We determined the effect of apigenin, a plant flavone, on IGF signaling and its downstream targets in TRAMP mice. Methods Mice received p.o. apigenin at 20 and 50µg/day dose for 20 weeks. ELISA, Western blotting and immunohistochemistry were performed to examine the IGF-axis and its regulated pathway in response to apigenin intake. Results Increased serum levels of IGF-I, VEGF, uPA and concomitant decrease in IGFBP3 were observed; p-Akt (Ser473), p-ERK1 (T202/Y204) and p-ERK2 (T185/Y187) expression increased in the dorso-lateral prostate of TRAMP mice during the course of cancer progression as a function of age. P.o. administration of apigenin resulted in substantial reduction in the levels of IGF-I and increase in the levels of IGFBP-3 in the serum and the dorso-lateral prostate. This modulation of IGF/IGFBP-3 was associated with an inhibition of p-Akt and p-ERK1/2. Apigenin intake resulted in marked inhibition of VEGF, uPA, MMP-2 and MMP-9 which coincided with tumor growth inhibition and complete absence of metastasis in TRAMP mice. Conclusions Our results indicate that apigenin effectively suppressed prostate cancer progression in TRAMP mice by attenuating IGF-I/IGFBP-3 signaling and inhibiting angiogenesis and metastasis.

show abstract

“…Apigenin is a potent inhibitor of several protein tyrosine kinases, including epidermal growth factor receptor and Src tyrosine kinase [27,28]. Apigenin has also been shown to modulate the expression of phosphatidylinositol 3-kinase, protein kinase B/Akt, mitogen-activated protein kinase, ERK1/2, casein kinase-2, and other upstream kinases involved in the development and progression of cancer [29][30][31]. Recently, our laboratory has demonstrated that apigenin sensitizes tumor cells to TNF-α-induced apoptosis through inhibition of NF-κB [32].…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Apigenin-induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation

Shukla

Gupta

2008

Free Radical Biology and Medicine

142

View full text Add to dashboard Cite

Apigenin, a plant flavone, potentially activates wild-type p53 and induces apoptosis in cancer cells. We conducted detailed studies to understand its mechanism of action. Exposure of human prostate cancer 22Rv1 cells, harboring wild-type p53, to growth-suppressive concentrations (10-80 μM) of apigenin resulted in the stabilization of p53 by phosphorylation on critical serine sites, p14 ARFmediated downregulation of MDM2 protein, inhibition of NF-κB/p65 transcriptional activity, and induction of p21/WAF-1 in a dose-and time-dependent manner. Apigenin at these doses resulted in ROS generation, which was accompanied by rapid glutathione depletion, disruption of mitochondrial membrane potential, cytosolic release of cytochrome c, and apoptosis. Interestingly, we observed accumulation of a p53 fraction to the mitochondria, which was rapid and occurred between 1 and 3 h after apigenin treatment. All these effects were significantly blocked by pretreatment of cells with the antioxidant N-acetylcysteine, p53 inhibitor pifithrin-α, and enzyme catalase. Apigenin-mediated p53 activation and apoptosis were further attenuated by p53 antisense oligonucleotide treatment. Exposure of cells to apigenin led to a decrease in the levels of Bcl-XL and Bcl-2 and increase in Bax, triggering caspase activation. Treatment with the caspase inhibitors Z-VAD-FMK and DEVD-CHO partially rescued these cells from apigenin-induced apoptosis. In vivo, apigenin administration demonstrated p53-mediated induction of apoptosis in 22Rv1 tumors. These results indicate that apigenin-induced apoptosis in 22Rv1 cells is initiated by a ROS-dependent disruption of the mitochondrial membrane potential through transcriptional-dependent and -independent p53 pathways. KeywordsReactive oxygen species; Apoptosis; p53; Prostate cancer; Apigenin; Free radicals Cancer prevention is profoundly dependent on the p53 tumor suppressor protein, as it functions in regulating cellular growth and protecting cells from malignant transformation [1,2]. Several studies have demonstrated the anticancer activities of p53, and in fact, p53 is the most *Corresponding author. Department of Urology, Case Western Reserve University, Cleveland, OH 44106, USA. Fax: +1 216 368 0213. E-mail address: sanjay.gupta@case.edu (S. Gupta). This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright NIH Public Access NIH-PA Author ManuscriptNIH-PA A...

show abstract

Unbalanced activation of ERK1/2 and MEK1/2 in apigenin-induced HeLa cell death

Cited by 31 publications

References 53 publications

Apigenin Inhibition of Involucrin Gene Expression Is Associated with a Specific Reduction in Phosphorylation of Protein Kinase Cδ Tyr311

Apigenin Inhibition of Involucrin Gene Expression Is Associated with a Specific Reduction in Phosphorylation of Protein Kinase Cδ Tyr311

Apigenin Attenuates Insulin-Like Growth Factor-I Signaling in an Autochthonous Mouse Prostate Cancer Model

Apigenin-induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation

Contact Info

Product

Resources

About