HGK promotes metastatic dissemination in prostate cancer

Garcia-Garcia, Sara; Rodrigo-Faus, María; Fonseca, Noelia; Manzano, Sara; Győrffy, Balázs; Ocaña, Alberto; Bragado, Paloma; Porrás, Almudena; Gutiérrez-Uzquiza, Álvaro

doi:10.1038/s41598-021-91292-2

Cited by 9 publications

(12 citation statements)

References 39 publications

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“…Naloxone-HCL, cyclic adenosine monophosphate (cAMP), GTPγS were purchased from Sigma-Aldrich (U.K). Phospho-ERK1/2 [42], vinculin [43] and Anti-NeuN [44] primary antibodies were purchased from Cell Signalling Technologies (U.S.A). All cell culture products were purchased from Thermofisher Scientific (UK).…”

Section: Methodsmentioning

confidence: 99%

MOP and NOP receptor interaction: Studies with a dual expression system and bivalent peptide ligands

et al. 2022

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Opioids targeting mu;μ (MOP) receptors produce analgesia in the peri-operative period and palliative care. They also produce side effects including respiratory depression, tolerance/dependence and addiction. The N/OFQ opioid receptor (NOP) also produces analgesia but is devoid of the major MOP side effects. Evidence exists for MOP-NOP interaction and mixed MOP-NOP ligands produce analgesia with reduced side effects. We have generated a HEKMOP/NOP human expression system and used bivalent MOP-NOP and fluorescent ligands to (i) probe for receptor interaction and (ii) consequences of that interaction. We used HEKMOP/NOP cells and two bivalent ligands; Dermorphin-N/OFQ (MOP agonist-NOP agonist; DeNO) and Dermorphin-UFP101 (MOP agonist-NOP antagonist; De101). We have determined receptor binding profiles, GTPγ[35S] binding, cAMP formation and ERK1/2 activation. We have also probed MOP and NOP receptor interactions in HEK cells and hippocampal neurones using the novel MOP fluorescent ligand, DermorphinATTO488 and the NOP fluorescent ligand N/OFQATTO594. In HEKMOP/NOP MOP ligands displaced NOP binding and NOP ligands displaced MOP binding. Using fluorescent probes in HEKMOP/NOP cells we demonstrated MOP-NOP probe overlap and a FRET signal indicating co-localisation. MOP-NOP were also co-localised in hippocampal tissue. In GTPγ[35S] and cAMP assays NOP stimulation shifted the response to MOP rightwards. At ERK1/2 the response to bivalent ligands generally peaked later. We provide evidence for MOP-NOP interaction in recombinant and native tissue. NOP activation reduces responsiveness of MOP activation; this was shown with conventional and bivalent ligands.

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Section: Methodsmentioning

confidence: 99%

MOP and NOP receptor interaction: Studies with a dual expression system and bivalent peptide ligands

et al. 2022

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“…Furthermore, increased IL-6 expression is associated with numerous neuropathological changes through either direct signaling or trans signaling via proteolytically shed, soluble IL-6 receptor ( 29 ). MAP4K4 induces TNFα and IL-1 production in macrophages and concomitant systemic inflammation ( 30 ), thereby possibly triggering a positive feedback via TNFα-induced MAP4K4 expression ( 31 , 32 ) and cell invasion in transformed cells ( 32 – 34 ). Finally, in CD4+ T cells KO for Map4k4, decreased IL-2 and interferon gamma (IFN γ) expression was noted ( 35 ).…”

Section: Introductionmentioning

confidence: 99%

“…MAP4K4 was identified as a broadly overexpressed kinase in human tumor cells ( 1 ) and has since then been recognized as an emerging target in cancer ( 10 ), in particular in solid tumors of epithelial tissues. Loss of function studies in gastric ( 55 ), hepatocellular carcinoma ( 56 ), prostate cancer ( 34 ) and pancreatic cancer cells ( 57 ) indicated tumorigenic and growth-promoting activities of MAP4K4. However, some of the described effects might be an indirect consequence of kinase function or – in the cases where miRNAs controlling MAP4K4 were investigated – of additional targets affected by the same miRNA.…”

Section: Introductionmentioning

confidence: 99%

The molecular basis of the dichotomous functionality of MAP4K4 in proliferation and cell motility control in cancer

Jovanović

Shen²,

Baumgärtner³

2022

Front. Oncol.

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The finely tuned integration of intra- and extracellular cues by components of the mitogen-activated protein kinase (MAPK) signaling pathways controls the mutually exclusive phenotypic manifestations of uncontrolled growth and tumor cell dissemination. The Ser/Thr kinase MAP4K4 is an upstream integrator of extracellular cues involved in both proliferation and cell motility control. Initially identified as an activator of the c-Jun N-terminal kinase (JNK), the discovery of diverse functions and additional effectors of MAP4K4 beyond JNK signaling has considerably broadened our understanding of this complex kinase. The implication of MAP4K4 in the regulation of cytoskeleton dynamics and cell motility provided essential insights into its role as a pro-metastatic kinase in cancer. However, the more recently revealed role of MAP4K4 as an activator of the Hippo tumor suppressor pathway has complicated the understanding of MAP4K4 as an oncogenic driver kinase. To develop a better understanding of the diverse functions of MAP4K4 and their potential significance in oncogenesis and tumor progression, we have collected and assessed the current evidence of MAP4K4 implication in molecular mechanisms that control proliferation and promote cell motility. A better understanding of these mechanisms is particularly relevant in the brain, where MAP4K4 is highly expressed and under pathological conditions either drives neuronal cell death in neurodegenerative diseases or cell dissemination in malignant tumors. We review established effectors and present novel interactors of MAP4K4, which offer mechanistic insights into MAP4K4 function and may inspire novel intervention strategies. We discuss possible implications of novel interactors in tumor growth and dissemination and evaluate potential therapeutic strategies to selectively repress pro-oncogenic functions of MAP4K4.

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“…Regarding lymph node dissection, we think that a more aggressive approach is currently suited for the patients with increased BMI, but we believe that further studies need to be corelated with the molecular mechanisms underlying PCa migration, in order to enable a better clinical, surgical and pharmacological management. Such molecular mechanisms were studied recently in vivo and revealed that the upregulation of HGK (a component of Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4), Culin 4B (a scaffold protein with oncogenic activity), overexpression of Human Homebox B9 (a key transcription factor that promotes metastases) and low levels of Receptor tyrosine kinase-like receptor (a noncanonical Wnt receptor) play a major role in the aggressive behavior of PCa [ 27 , 28 , 29 , 30 ]. Our data about the radical prostatectomy, orchiectomy, lymphadenectomy and pathological staging is limited because the surgeries and the histopathological exam were performed in other hospitals.…”

Section: Discussionmentioning

confidence: 99%

Associations between Body Mass Index and Prostate Cancer: The Impact on Progression-Free Survival

et al. 2023

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Background and objectives: This study aimed to evaluate the impact of body mass index on PCa outcomes in our institution and also to find if there are statistically significant differences between the variables. Materials and Methods: A retrospective chart review was performed to extract information about all male patients with prostate cancer between 1 February 2015, and 25 October 2022, and with information about age, weight, height, follow-up, and PSA. We identified a group of 728 patients, of which a total of 219 patients resulted after the inclusion and exclusion criteria were applied. The primary endpoint was progression-free survival, which was defined as the length of time that the patient lives with the disease, but no relapses occur, and this group included 105 patients. In this case, 114 patients had a biological, local or metastatic relapse and were included in the progression group. Results: Our study suggests that prostate cancer incidence rises with age (72 ± 7.81 years) in men with a normal BMI, but the diagnostic age tends to drop in those with higher BMIs, i.e., overweight, and obese in the age range of 69.47 ± 6.31 years, respectively, 69.1 ± 7.51 years. A statistically significant difference was observed in the progression group of de novo metastases versus the absent metastases group at diagnostic (p = 0.04). The progression group with metastases present (n = 70) at diagnostic had a shorter time to progression, compared to the absent metastases group (n = 44), 18.04 ± 11.37 months, respectively, 23.95 ± 16.39 months. Also, PSA levels tend to diminish with increasing BMI classification, but no statistically significant difference was observed. Conclusions: The median diagnostic age decreases with increasing BMI category. Overweight and obese patients are more likely to have an advanced or metastatic prostate cancer at diagnosis. The progression group with metastatic disease at diagnostic had a shorter time to progression, compared to the absent metastases group. Regarding prostate serum antigen, the levels tend to become lower in the higher BMI groups, possibly leading to a late diagnosis.

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HGK promotes metastatic dissemination in prostate cancer

Cited by 9 publications

References 39 publications

MOP and NOP receptor interaction: Studies with a dual expression system and bivalent peptide ligands

MOP and NOP receptor interaction: Studies with a dual expression system and bivalent peptide ligands

The molecular basis of the dichotomous functionality of MAP4K4 in proliferation and cell motility control in cancer

Associations between Body Mass Index and Prostate Cancer: The Impact on Progression-Free Survival

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