Death-associated protein kinase 1 promotes growth of p53-mutant cancers

Zhao, Jing; Zhao, Daqing; Poage, Graham M.; Mazumdar, Abhijit; Zhang, Yun; Hill, Jamal; Hartman, Zachary C.; Savage, Michelle I.; Mills, Gordon B.; Brown, Powel H.

doi:10.1172/jci70805

Cited by 56 publications

(63 citation statements)

References 46 publications

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“…In both cases, there were significant differences between the protein levels in the breast cancer cases and the controls ( p < 0.05). On the part of vimentin, earlier reports suggest that there is elevated expression of the protein in breast cancer cell lines and tissues and also in several aggressive breast cancer cell lines [27, 31]. This is in line with findings from this study as observed in Fig.…”

Section: Discussionsupporting

confidence: 93%

Higher serum concentrations of vimentin and DAKP1 are associated with aggressive breast tumour phenotypes in Ghanaian women

et al. 2017

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BackgroundBreast cancer, the most commonly diagnosed cancer among women and leading cause of cancer-related deaths worldwide, exhibits aggressive behavior in indigenous African women evidenced by high histologic grade tumours with low hormone receptor positivity. Aggressive breast cancers grow quickly, easily metastasize and recur and often have unfavourable outcomes. The current study investigated candidate genes that may regulate tumour aggression in Ghanaian women. We hypothesize that increased expression and function of certain genes other than the widely-held view attributing breast cancer aggression in African populations to their younger population age may be responsible for the aggressive nature of tumours.MethodsEmploying ELISA, we assayed for vimentin and death-associated protein kinase 1 (DAPK1) from thawed archived (stored at -80 °C) serum samples obtained from 40 clinically confirmed Ghanaian breast cancer patients and 40 apparently healthy controls. Patients’ clinical records and tumour parameters matching the samples were retrieved from the database of the hospital. ANOVA was used to compare means of serum protein concentration among groups while Chi-square analysis was used for the categorical data sets with p-value ≤0.05 considered significant. Multiple logistic regression analysis was conducted to determine the association between protein concentration and tumour parameters.ResultsOf the 80 samples, 27 (33.8%) and 53 (66.2%) were from young (<35 years) and old (≥35 years), respectively. Vimentin and DAPK1 concentration were higher in patients than controls with higher levels in “young” age group than “old” age group. Vimentin concentration was highest in grade 3 tumours followed by grade 2 and 1 but that for DAPK1 was not significant. For vimentin, tumour area strongly correlated with tumour grade (r = 0.696, p < 0.05) but weakly correlated with tumour stage (r = 0.420, p < 0.05). Patient’s age correlated with DAPK1 concentration (r = 0.393, p < 0.05). DAPK1 serum levels weakly correlated with cancer duration (r = 0.098, p = 0.27) and tumour size (r = 0.40, p < 0.05).ConclusionSerum concentration of Vimentin and DAPK1 are elevated in Ghanaian breast cancer patients. This may be partly responsible for aggressive nature of the disease among the population. Vimentin and DAPK1 should be explored further as potential breast cancer biomarkers in Africans.

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Section: Discussionsupporting

confidence: 93%

Higher serum concentrations of vimentin and DAKP1 are associated with aggressive breast tumour phenotypes in Ghanaian women

et al. 2017

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“…It has been shown to be highly expressed in ER negative breast cancers when compared to ER positive breast cancers (125). Recent studies suggest that DAPK1 is essential for growth of p53-mutant cancers, which account for over 80% of TNBCs.…”

Section: Targeting Pathways That Are Critical For Growth Of P53-mutanmentioning

confidence: 99%

Molecularly targeted therapies for p53-mutant cancers

Zhao

Tahaney

Mazumdar

et al. 2017

Cell. Mol. Life Sci.

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The tumor suppressor p53 is lost or mutated in approximately half of human cancers. Mutant p53 not only loses its anti-tumor transcriptional activity, but often acquires oncogenic functions to promote tumor proliferation, invasion, and drug resistance. Traditional strategies have been taken to directly target p53 mutants through identifying small molecular compounds to deplete mutant p53, or to restore its tumor suppressive function. Accumulating evidence suggest that cancer cells with mutated p53 often exhibit specific functional dependencies on secondary genes or pathways to survive, providing alternative targets to indirectly treat p53-mutant cancers. Targeting these genes or pathways, critical for survival in the presence of p53 mutations, holds great promise for cancer treatment. In addition, mutant p53 often exhibits novel gain-of-functions to promote tumor growth and metastasis. Here, we review and discuss strategies targeting mutant p53, with focus on targeting the mutant p53 protein directly, and on the progress of identifying genes and pathways required in p53-mutant cells.

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“…Proteins such as p21 and p53 have been shown to serve as substrates for DAPK1 . In addition, multiple highly aggressive cancers with p53 mutations could be effectively treated with DAPK1 inhibitors . According to these findings, we detected p53 protein expression and found that both miR‐98 over‐expression and DAPK1 depletion could reduce the elevation level of p53 induced by H/R.…”

Section: Discussionmentioning

confidence: 87%

MicroRNA‐98 attenuates cardiac ischemia‐reperfusion injury through inhibiting DAPK1 expression

et al. 2018

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Cardiovascular ischemic disease is a large class of diseases that are harmful to human health. The significant role of microRNAs (miRNAs) in terms of controlling cardiac injury has been reported in latest studies. MiR‐98 is very important in regulating the apoptosis, the differentiation, the growth as well as the metastasis of cells. Nevertheless, the effect of miR‐98 in the cardiac ischemia reperfusion (I/R) injury has rarely been investigated. In the current research, we found that the miR‐98 expression was down‐regulated in the cardiomyocytes subjected to hypoxia/reoxygenation (H/R) and in the myocardium of the I/R rats. In addition, over‐expression of miR‐98 could significantly reduce the myocardial oxidative stress and ischemic injury as well as cell apoptosis. In agreement, similar findings were demonstrated in H9c2 cells subjected to H/R injury. Bioinformatic analysis using MiRanda and TargetScan and luciferase activity assay confirmed death‐associated protein kinase 1 (DAPK1) as a direct target of miR‐98. These findings suggest that miR‐98 may be exploited as a novel molecular marker or therapeutic target for myocardial I/R injury. © 2018 IUBMB Life, 71(1):166–176, 2019

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Death-associated protein kinase 1 promotes growth of p53-mutant cancers

Cited by 56 publications

References 46 publications

Higher serum concentrations of vimentin and DAKP1 are associated with aggressive breast tumour phenotypes in Ghanaian women

Higher serum concentrations of vimentin and DAKP1 are associated with aggressive breast tumour phenotypes in Ghanaian women

Molecularly targeted therapies for p53-mutant cancers

MicroRNA‐98 attenuates cardiac ischemia‐reperfusion injury through inhibiting DAPK1 expression

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