Apoptotic effect of lambertianic acid through <scp>AMPK/FOXM1</scp> signaling in <scp>MDA‐MB231</scp> breast cancer cells

Lee, Jae Hee; Sim, Deok Yong; Jung, Ji Hoon; Kim, Ka Ram; Kim, Sung‐Hoon

doi:10.1002/ptr.6105

Cited by 21 publications

(20 citation statements)

References 37 publications

(44 reference statements)

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“…Since the 24-AMPK-gene set was a positive prognostic factor in glioma where high expression of the genes was associated with better outcomes ( Figure 2C), glioma patients harboring low AMPK scores and high oncogenic TF scores performed the worst. Our results are confirmed by other reports on the crosstalk between AMPK signaling and E2F4, EZH2, FOXMI or SUZ12 and their effects on oncogenic progression (42)(43)(44)(45). Our analyses on SMAD4 in glioma revealed a likely tumor-suppressive role of the gene ( Figure 6B), which is corroborated by another study demonstrating reduced SMAD4 expression during glioma tumor progression (46).…”

Section: Discussionsupporting

confidence: 91%

An integrative pan-cancer investigation reveals common genetic and transcriptional alterations of AMPK pathway genes as important predictors of clinical outcomes across major cancer types

Lai

2019

Preprint

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The AMP-activated protein kinase (AMPK) is an evolutionarily conserved regulator of cellular energy homeostasis. As a nexus for transducing metabolic signals, AMPK cooperates with other energy-sensing pathways to modulate cellular responses to metabolic stressors. With metabolic reprogramming being a hallmark of cancer, the utility of agents targeting AMPK has received continued scrutiny and results have demonstrated conflicting effects of AMPK activation in tumorigenesis. Harnessing multi-omics datasets from human tumors, we seek to evaluate the seemingly pleiotropic, tissue-specific dependencies of AMPK signaling dysregulation. We interrogated copy number variation and differential transcript expression of 92 AMPK pathway genes across 21 diverse cancers involving over 18,000 patients. Cox proportional hazards regression and receiver operating characteristic analyses were used to evaluate the prognostic significance of AMPK dysregulation on patient outcomes. A total of 24 and seven AMPK pathway genes were identified as having loss-or gain-of-function features. These genes exhibited tissue-type dependencies, where survival outcomes in glioma patients were most influenced by AMPK inactivation. Cox regression and log-rank tests revealed that the 24-AMPKgene set could successfully stratify patients into high-and lowrisk groups in glioma, sarcoma, breast and stomach cancers. The 24-AMPK-gene set could not only discriminate tumor from non-tumor samples, as confirmed by multidimensional scaling analyses, but is also independent of tumor, node and metastasis staging. AMPK inactivation is accompanied by the activation of multiple oncogenic pathways associated with cell adhesion, calcium signaling and extracellular matrix organization. Anomalous AMPK signaling converged on similar groups of transcriptional targets where a common set of transcription factors were identified to regulate these targets. We also demonstrated crosstalk between pro-catabolic AMPK signaling and two pro-anabolic pathways, mammalian target of rapamycin and peroxisome proliferator-activated receptors, where they act synergistically to influence tumor progression significantly. Genetic and transcriptional aberrations in AMPK signaling have tissue-dependent pro-or anti-tumor impacts. Pan-cancer investigations on molecular changes of this pathway could uncover novel therapeutic targets and support risk stratification of patients in prospective trials. AMPK | Glioma | Loss-of-function | Tumor metabolism | Pan-cancerCorrespondence: alvina.lai@ucl.ac.uk

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Section: Discussionsupporting

confidence: 91%

An integrative pan-cancer investigation reveals common genetic and transcriptional alterations of AMPK pathway genes as important predictors of clinical outcomes across major cancer types

Lai

2019

Preprint

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“…This might have been responsible for the greater pro-apoptotic influence of AICAR in MDA-MB-231 cells. This was also consistent with the reported apoptotic influence of AMPK activation in MDA-MB-231 cells, which was mediated by inhibition of Akt/FOXM1 signalling (Lee et al, 2018). Cell cycle analysis in T47D cells showed that AICAR-activated AMPK affected cell proliferation by induction of both cell cycle arrest and apoptosis ( Figure 5).…”

Section: Discussionsupporting

confidence: 90%

AMPK Activation of Apoptotic Markers in Human Breast Cancer Cell Lines with Different p53 Backgrounds: MCF-7, MDA-MB-231 and T47D Cells

El‐Masry

Brown

Dobson

2019

Asian Pac J Cancer Prev

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Background: Downregulation of AMPK has been established as a major contributor to carcinogenesis in many types of human cancer. We sought to investigate the influence of activated AMPK on apoptotic markers in human breast cancer cells differing in their p53 status, as well as estrogen receptor status (MCF-7 (p53+ and ER+), MDA-MB-231 (p53 mutant and ER-) and T47D (p53 mutant and ER+)). Methods: We examined the effect of AICAR-activated AMPK on PARP cleavage, Bax redistribution, the involvement of intrinsic and extrinsic pathways of apoptosis using selective caspase inhibitors and cell cycle progression and p21 levels. Results: PARP cleavage occurred to a greater extent in MCF-7 and MDA-MB-231 cells, whereas Bax translocation was slower in MDA-MB-231 cells. Although there were quantitative differences in the effect of caspase inhibitors, it was clear that AMPK activation predominately affected the intrinsic pathway of apoptosis. Although, p21 was increased in all 3 cell types, there were quantitative and time differences. Apoptosis, as measured by fluorimetry, was increased in all three cell types. Conclusion: The impact of AMPK activation was cell type dependent resulting in differential activation of apoptotic markers, confirming that the genetic background of breast cancer may have an influence on the mode of action of AMPK. Thus, different anti-tumour mechanisms may be elicited depending on the cellular genotype.

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“…In fact, the AMPK signaling pathway has been proved to be strongly linked to various tumors such as HCC. 24,25 Further study of gene expression in the HCC database from the TCGA website ( Figure 1D) revealed that the Rab10 gene was highly expressed in multiple stages of HCC, which matched the observations from Rab10 gene expression in the GSE49515 microarray data. To further understand the upstream regulatory mechanisms of the Rab10 gene, databases such as miRDB were used to predict regulatory miRNAs for Rab10.…”

Section: The Role Of Rab10 As An Oncogene In Hccsupporting

confidence: 71%

<p>microRNA-519d Induces Autophagy and Apoptosis of Human Hepatocellular Carcinoma Cells Through Activation of the AMPK Signaling Pathway via Rab10</p>

Zhang¹,

Pan²,

Yu³

et al. 2020

CMAR

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Background and Aim: Hepatocellular carcinoma (HCC) is a type of cancer with high mortality rates. The overexpression of microRNA-519d (miR-519d) has been explored in different types of cancers, which could significantly help suppress cancer development. This study aimed to investigate the interaction of miR-519d with its target gene, Rab10, as well as its effects on cell proliferation and autophagy in HCC cells through modulation of the AMPK signaling pathway. Methods: Microarray analysis was used to analyze the differentially expressed genes in HCC, and the target genes of the screened-out miRNA were predicted and verified. The expression of miR-519d and Rab10, AMPK signaling pathway-related proteins, apoptosisand autophagy-related proteins was determined by RT-qPCR and Western blot analysis in HCC tissues and cell lines. Lastly, the effects of miR-519d and Rab10 in HCC cell proliferation, apoptosis, and mouse tumour xenograft in vivo were examined through gainand loss-of-function experiments. Results: MiR-519d was down-regulated and Rab10 was upregulated in HCC tissues and cell lines. Overexpression of miR-519d decreased the expression of Rab10, mTOR, and Bcl-2, but increased the expression of Bax, Beclin1, Atg5, and p53. Upregulated miR-519d and downregulated Rab10 expression suppressed cell proliferation and induced cell apoptosis and autophagy in HCC cells. Finally, upregulation of miR-519d inhibited tumour growth in vivo. Conclusion: The result obtained in this study indicates that up-regulation of miR-519d inhibits proliferation and promotes apoptosis and autophagy of HCC cells through activation of the AMPK signaling pathway via downregulating Rab10, which provides a potential target for the treatment of HCC.

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Apoptotic effect of lambertianic acid through AMPK/FOXM1 signaling in MDA‐MB231 breast cancer cells

Cited by 21 publications

References 37 publications

An integrative pan-cancer investigation reveals common genetic and transcriptional alterations of AMPK pathway genes as important predictors of clinical outcomes across major cancer types

An integrative pan-cancer investigation reveals common genetic and transcriptional alterations of AMPK pathway genes as important predictors of clinical outcomes across major cancer types

AMPK Activation of Apoptotic Markers in Human Breast Cancer Cell Lines with Different p53 Backgrounds: MCF-7, MDA-MB-231 and T47D Cells

<p>microRNA-519d Induces Autophagy and Apoptosis of Human Hepatocellular Carcinoma Cells Through Activation of the AMPK Signaling Pathway via Rab10</p>

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