AMPK expression patterns are significantly associated with poor prognosis in breast cancer patients

Al-Maghrabi, Jaudah; Al-Sakkaf, Kaltoom; Qureshi, Imtiaz Ahmad; Butt, Nadeem Shafique; Damnhory, Lila; Elshal, Mohamed F.; Al-Maghrabi, Basim; Aldahlawi, Alia; Ashoor, Sawsan; Brown, Barry L.; Dobson, Pauline R.M.

doi:10.1016/j.anndiagpath.2017.05.012

Cited by 14 publications

(12 citation statements)

References 37 publications

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“…Current efforts are focused on developing drugs that specifically target proteins or pathways that are exclusively altered in TNBC. Since expression of AMPK and pAMPK is lower in breast cancer than normal tissue, this signaling pathway attracted our attention as an option for targeted therapy [30–32].…”

Section: Discussionmentioning

confidence: 99%

Induction of AMPK activation by N,N’-diarylurea FND-4b decreases growth and increases apoptosis in triple negative and estrogen-receptor positive breast cancers

et al. 2019

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PurposeTriple negative breast cancer (TNBC) is the most lethal and aggressive subtype of breast cancer. AMP-activated protein kinase (AMPK) is a major energy regulator that suppresses tumor growth, and 1-(3-chloro-4-((trifluoromethyl)thio)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea (FND-4b) is a novel AMPK activator that inhibits growth and induces apoptosis in colon cancer. The purpose of this project was to test the effects of FND-4b on AMPK activation, proliferation, and apoptosis in breast cancer with a particular emphasis on TNBC.Materials and methods(i) Estrogen-receptor positive breast cancer (ER+BC; MCF-7, and T-47D), TNBC (MDA-MB-231 and HCC-1806), and breast cancer stem cells were treated with FND-4b for 24h. Immunoblot analysis assessed AMPK, acetyl-CoA carboxylase (ACC), ribosomal protein S6, cyclin D1, and cleaved PARP. (ii) Sulforhodamine B growth assays were performed after treating ER+BC and TNBC cells with FND-4b for 72h. Proliferation was also assessed by counting cells after 72h of FND-4b treatment. (iii) Cell death ELISA assays were performed after treating ER+BC and TNBC cells with FND-4b for 72h.Results(i) FND-4b increased AMPK activation with concomitant decreases in ACC activity, phosphorylated S6, and cyclin D1 in all subtypes. (ii) FND-4b decreased proliferation in all cells, while dose-dependent growth decreases were found in ER+BC and TNBC. (iii) Increases in apoptosis were observed in ER+BC and the MDA-MB-231 cell line with FND-4b treatment.ConclusionsOur findings indicate that FND-4b decreases proliferation for a variety of breast cancers by activating AMPK and has notable effects on TNBC. The growth reductions were mediated through decreases in fatty acid synthesis (ACC), mTOR signaling (S6), and cell cycle flux (cyclin D1). ER+BC cells were more susceptible to FND-4b-induced apoptosis, but MDA-MB-231 cells still underwent apoptosis with higher dose treatment. Further development of FND compounds could result in a novel therapeutic for TNBC.

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Section: Discussionmentioning

confidence: 99%

Induction of AMPK activation by N,N’-diarylurea FND-4b decreases growth and increases apoptosis in triple negative and estrogen-receptor positive breast cancers

et al. 2019

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“…Tissue microarrays were made from 155 colorectal cancer cases and 73 control tissue specimens as mentioned in our earlier papers. [ 26 , 27 ] TMA blocks have been sliced into 4 micron sections and sited on glass slides coated with aminosilane. Later, it was employed in leptin immunohistochemistry staining protocol.…”

Section: Methodsmentioning

confidence: 99%

“…Immunohistochemical analysis was applied using immunohistochemistry autostainer (BenchMark ULTRA, Ventana, AZ) as previously reported. [ 26 , 27 ] Antileptin rabbit polyclonal antibody with dilution ratio of 1 to 100 (Santa Cruz Biotechnology), then ULTRAVIEW TM DAB visualizing protocol were used in immunohistochemistry staining. Every staining run contained a slide treated with tris buffer rather than antileptin antibody for using it as a negative control.…”

Section: Methodsmentioning

confidence: 99%

Expression of leptin in colorectal adenocarcinoma showed significant different survival patterns associated with tumor size, lymphovascular invasion, distant metastasis, local recurrence, and relapse of disease in the western province of Saudi Arabia

Al-Maghrabi

Qureshi²,

Khabaz³

2018

Medicine

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Leptin phenotype has been suggested to be a possible biomarker for the diagnosis and prognosis of different neoplasms. Nonetheless, there are conflicts among the outcomes found in several tumors, and little is proven concerning the correlation between the phenotype of leptin and its clinical significance in colorectal carcinomas. This study will describe the phenotype of leptin in colorectal adenocarcinomas, and investigate its correlation with clinicopathological factors.Two hundred and twenty eight tissue samples include 155 colorectal carcinomas, 40 adenomas, and 33 noncancerous cases were utilized in constructing tissue microarrays which have been used in the revealing of leptin expression using leptin monoclonal antibody and immunohistochemistry staining protocol.Immunoexpression of leptin was recognized in 145 (93.5%) of colorectal tumors and 56 (76.7%) cases of control group. Histotype was considerably associated with leptin phenotype (P = .000), there is up regulation in leptin expression in colorectal carcinoma cases. Significantly higher proportion of negative leptin immunostaining cases were observed in tumors which have size more than 5 cm (P = .045). Whereas, significant different survival patterns were observed in positive cases regarding tumor size, lymphovascular invasion, distant metastasis, local recurrence and relapse of disease (P-values .046, .011, .000, .013, and .001, respectively). On the other hand, positive leptin staining colorectal tumors with size <5 cm, and with no distant metastases, local recurrence, or disease relapse had significantly better survival estimates. However, leptin immunostaining did not show noteworthy associations with age, gender, differentiation, tumor location, stage, margins involvement, lymphovascular invasion, and lymph node metastasis.The current study shows up regulation in leptin expression in colorectal adenocarcinoma compared with noncancerous control cases. Thus, immunohistochemical staining of leptin in colorectal cancer could be a helpful tool in the prediction of prognosis and survival pattern of colorectal cancer with certain clinicopathological factors (tumor size, lymphovascular invasion, distant metastasis, local recurrence, and relapse of disease).

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“…AMP-activated protein kinase (AMPK), a ubiquitous metabolic regulator, has emerged as an enzyme having numerous regulatory functions both centrally (Andersson et al, 2004;Anderson et al, 2008;Chikahisa et al, 2009) and peripherally (Fryer et al, 2002;Assifi et al, 2005;Kahn et al, 2005), including control of cell growth and survival (Motoshima et al, 2006;El-Masry et al, 2012;Hardie and Alessi, 2013). AMPK has been reported to be both a biomarker by us and others (Huang et al, 2016;Al-Maghrabi et al, 2017) and a therapeutic target (Cao et al, 2019). In addition, we have shown crosstalk between AMPK and the anti-apoptotic PI3 kinase pathway in breast cancer cells (El-Masry et al, 2015).…”

Section: Introductionmentioning

confidence: 88%

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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AMPK expression patterns are significantly associated with poor prognosis in breast cancer patients

Cited by 14 publications

References 37 publications

Induction of AMPK activation by N,N’-diarylurea FND-4b decreases growth and increases apoptosis in triple negative and estrogen-receptor positive breast cancers

Induction of AMPK activation by N,N’-diarylurea FND-4b decreases growth and increases apoptosis in triple negative and estrogen-receptor positive breast cancers

Expression of leptin in colorectal adenocarcinoma showed significant different survival patterns associated with tumor size, lymphovascular invasion, distant metastasis, local recurrence, and relapse of disease in the western province of Saudi Arabia

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

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