Asiatic Acid, a Triterpene, Induces Apoptosis and Cell Cycle Arrest through Activation of Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase Pathways in Human Breast Cancer Cells

Hsu, Ya Ling; Kuo, Po Lin; Lin, Liang; Lin, Chih‐Hsueh

doi:10.1124/jpet.104.078808

Cited by 208 publications

(148 citation statements)

References 33 publications

(35 reference statements)

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“…Many cytotoxic agents induce a prolonged activation of ERK required for induction of apoptosis or cell cycle arrest (Tang et al, 2002;Xiao and Singh, 2002;Hsu et al, 2005;Chambard et al, 2007). The role of ERK activity in these cellular responses has been confirmed using mitogen-activated protein kinase kinase-1 inhibitors.…”

Section: Discussionmentioning

confidence: 95%

Insulin-Like Growth Factor Type-I Receptor-Dependent Phosphorylation of Extracellular Signal-Regulated Kinase 1/2 but not Akt (Protein Kinase B) Can Be Induced by Picropodophyllin

Vasilcanu

Vasilcanu²,

Sehat³

et al. 2007

Mol Pharmacol

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The initial event upon binding of insulin-like growth factor 1 to the insulin-like growth factor type-I receptor (IGF-1R) is autophosphorylation of tyrosine residues within the activation loop of the kinase domain followed by phosphorylation of other receptor tyrosine residues and the subsequent activation of the intracellular signaling cascades. We found recently that the cyclolignan picropodophyllin (PPP) inhibits phosphorylation of IGF-1R and phosphatidyl-3 kinase/Akt (protein kinase B) signaling molecules without interfering with the highly homologous insulin receptor. Furthermore, PPP causes regression of tumor grafts and substantially prolongs the survival of animals with systemic tumor disease. It is of interest that we show here that short treatments with PPP activate the intracellular extracellular signal-regulated kinase (ERK) signaling. Our data suggest that PPP induces IGF-1R ubiquitination and in turn activates ERK1/2. The PPP-induced ERK activation requires IGF-1R because PPP is not able to induce ERK phosphorylation in IGF-1R-negative cells or in cells in which the receptor is knocked down by small interfering RNA. Moreover, in the absence of Mdm2, an E3 ligase that has been shown previously to be involved in IGF-1R ubiquitination, the phosphorylation of ERK did not occur. Thus, apart from inhibiting the receptor activity, PPP can induce IGF-1R ubiquitination and stimulate ERK in an Mdm2-dependent manner. This response could contribute to the apoptotic effect of PPP.

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Section: Discussionmentioning

confidence: 95%

Insulin-Like Growth Factor Type-I Receptor-Dependent Phosphorylation of Extracellular Signal-Regulated Kinase 1/2 but not Akt (Protein Kinase B) Can Be Induced by Picropodophyllin

Vasilcanu

Vasilcanu²,

Sehat³

et al. 2007

Mol Pharmacol

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“…In addition, asiatic acid activated phosphorylated p38 kinase and correspondingly induced cell cycle arrest and triggered apoptosis in MCF-7 and MDA-MB-231 cells, respectively. Interestingly, in the same study it was shown that ERK1/2 was activated in asiatic acid-mediated apoptosis in breast cancer cells (Hsu et al, 2005). Similarly, another chemotherapeutic agent, rotenone, which is an inhibitor of the mitochondrial electron transport chain complex I, caused the activation of JNK and p38 and the inactivation of ERK1/2 to induce apoptosis in MCF-7 cells (Deng et al, 2010).…”

Section: Discussionmentioning

confidence: 92%

Downregulation of c-Myc mediated ODC expression after purvalanol treatment is under control of upstream MAPK signaling axis in MCF-7 breast cancer cells

Obakan¹,

Alkurt²,

Köse³

et al. 2014

Turk J Biol

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IntroductionMammalian cell division, mitotic transfer of genome to new daughter cells, occurs when the cell has enough cytoplasmic content and DNA replication is finished correctly. The regulatory mechanisms during interphase (G1, S, G2 phases) control the cell division decision by the presence of various time-dependent and regularly activated molecules such as cyclin and cyclin-dependent kinases (CDKs) (Morgan et al., 1998). Each interphase phase has its own activated cyclin-CDK complexes that permit cell cycle progression during surveillance mechanisms (Arellano et al., 1997). Growth promoting signals due to growth factors change the cell cycle regulation and promote neoplastic transformation (Paulovich et al., 1997). Recently, new approaches to antineoplastic therapy are focused on cyclin-CDK complex inhibition.Thus far, 6 classes of chemical CDK inhibitors have been characterized, including purine-derived CDK inhibitors (Meijer, 1996). Olomoucine, roscovitine, and purvalanol are the most commonly investigated CDK inhibitors that cause cell cycle arrest and trigger apoptotic cell death. Roscovitine (CYC202, Seliciclib) or purvalanol induce apoptosis by causing cell cycle arrest in the G1 and G2/M phases in prostate (Ringer et al., 2010), lung (Zhang et al., 2010, multiple myeloma (Komina et al., 2011), colon, and breast cancer cell lines (Wesierska-Gadek et al., 2004;Arisan et al., 2012). Although CDK inhibitor-induced apoptotic cell death has been determined in breast cancer, the exact underlying molecular targets in cell death and survival mechanism have not been clarified yet.MAPKs are regulated by various cellular arrangements such as cell growth, differentiation, and apoptotic cell Abstract: Roscovitine and purvalanol are specific cyclin-dependent kinase (CDK) inhibitors, which induce apoptosis by triggering cell cycle arrest in various cancer cells such as colon, prostate, and breast cancer cells. Although the apoptotic action of roscovitine was clarified at the molecular level, the exact mechanism of purvalanol-induced apoptosis is still under investigation. The mitogenactivated protein kinase (MAPK) signaling cascade is activated by different inducers related to growth, proliferation, differentiation processes, or environmental stress factors. Recent reports showed that modulation of MAPKs might lead to regulation of c-Myc, which is a transcription factor for the polyamine (PA) biosynthesis enzyme, ornithine decarboxylase (ODC). PAs are amine-derived cationic molecules that play crucial roles in cell proliferation, growth, and differentiation. In this study, we investigated the potential role of the MAPK signaling cascade in the purvalanol-induced apoptosis mechanism by comparing the results of roscovitine in MCF-7 and MDA-MB-231 breast cancer cells. We found that CDK inhibitors decreased the cell viability in a dose-and time-dependent manner in MCF-7 and MDA-MB-231 cancer cells. Although both CDK inhibitors induced cell cycle arrest, which led to apoptosis by activating caspases and PARP cleavage in ...

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“…Pentacyclic triterpenoids have been found to have wide-ranging pharmacological effects and in particular AA has been shown to reduce inflammation, inhibit tumor cell proliferation, and induce apoptosis through a mitochondria-dependent pathway [18]. Its anti-cancer efficacy is attributed to its ability to inhibit transcription factor NF-jB, p38 MAP and ERK kinases in a variety of tumor cells [18][19][20][21]. AA induced apoptotic cell death in human hepatoma and malignant glioma cells through enhancing intracellular calcium release [22,23].…”

Section: Asiatic Acidmentioning

confidence: 99%

Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer

et al. 2012

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a b s t r a c tOver the last two decades, extensive research on plant-based medicinal compounds has revealed exciting and important pharmacological properties and activities of triterpenoids. Fruits, vegetables, cereals, pulses, herbs and medicinal plants are all considered to be biological sources of these triterpenoids, which have attracted great attention especially for their potent anti-inflammatory and anti-cancer activities. Published reports in the past have described the molecular mechanism(s) underlying the various biological activities of triterpenoids which range from inhibition of acute and chronic inflammation, inhibition of tumor cell proliferation, induction of apoptosis, suppression of angiogenesis and metastasis. However systematic analysis of various pharmacological properties of these important classes of compounds has not been done. In this review, we describe in detail the pre-clinical chemopreventive and therapeutic properties of selected triterpenoids that inhibit multiple intracellular signaling molecules and transcription factors involved in the initiation, progression and promotion of various cancers. Molecular targets modulated by these triterpenoids comprise, cytokines, chemokines, reactive oxygen intermediates, oncogenes, inflammatory enzymes such as COX-2, 5-LOX and MMPs, anti-apoptotic proteins, transcription factors such as NF-jB, STAT3, AP-1, CREB, and Nrf2 (nuclear factor erythroid 2-related factor) that regulate tumor cell proliferation, transformation, survival, invasion, angiogenesis, metastasis, chemoresistance and radioresistance. Finally, this review also analyzes the potential role of novel synthetic triterpenoids identified recently which mimic natural triterpenoids in physical and chemical properties and are moving rapidly from bench to bedside research.

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Asiatic Acid, a Triterpene, Induces Apoptosis and Cell Cycle Arrest through Activation of Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase Pathways in Human Breast Cancer Cells

Cited by 208 publications

References 33 publications

Insulin-Like Growth Factor Type-I Receptor-Dependent Phosphorylation of Extracellular Signal-Regulated Kinase 1/2 but not Akt (Protein Kinase B) Can Be Induced by Picropodophyllin

Insulin-Like Growth Factor Type-I Receptor-Dependent Phosphorylation of Extracellular Signal-Regulated Kinase 1/2 but not Akt (Protein Kinase B) Can Be Induced by Picropodophyllin

Downregulation of c-Myc mediated ODC expression after purvalanol treatment is under control of upstream MAPK signaling axis in MCF-7 breast cancer cells

Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer

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