scholarly journals Wnt/β-catenin signal transduction pathway in prostate cancer and associated drug resistance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chunyang Wang ◽  
Qi Chen ◽  
Huachao Xu
Keyword(s):  
Prostate Cancer ◽  
Signal Transduction ◽  
Drug Resistance ◽  
Androgen Receptor ◽  
Signal Transduction Pathway ◽  
Transduction Pathway ◽  
Cancer Pathogenesis ◽  
Asian Men ◽  
Therapy Development ◽  
The Impact

AbstractGlobally, prostate cancer ranks second in cancer burden of the men. It occurs more frequently in black men compared to white or Asian men. Usually, high rates exist for men aged 60 and above. In this review, we focus on the Wnt/β-catenin signal transduction pathway in prostate cancer since many studies have reported that β-catenin can function as an oncogene and is important in Wnt signaling. We also relate its expression to the androgen receptor and MMP-7 protein, both critical to prostate cancer pathogenesis. Some mutations in the androgen receptor also impact the androgen-β-catenin axis and hence, lead to the progression of prostate cancer. We have also reviewed MiRNAs that modulate this pathway in prostate cancer. Finally, we have summarized the impact of Wnt/β-catenin pathway proteins in the drug resistance of prostate cancer as it is a challenging facet of therapy development due to the complexity of signaling pathways interaction and cross-talk.

scholarly journals Androgen receptor pathway activity assay for sepsis diagnosis and prediction of favorable prognosis.

2021 ◽  
Author(s):  
Wilbert Bouwman ◽  
Wim Verhaegh ◽  
Anja van de Stolpe
Keyword(s):  
Signal Transduction ◽  
Androgen Receptor ◽  
Bacterial Infection ◽  
Signal Transduction Pathway ◽  
Transduction Pathway ◽  
Activity Assay ◽  
Pathway Activity ◽  
Sepsis Diagnosis ◽  
Favorable Prognosis ◽  
Tgfβ Pathway

Introduction Sepsis is a life-threatening complication of a bacterial infection. Accurate and timely diagnosis, as well as prognosis-prediction, is difficult. It is hard to predict which patients with a bacterial infection will develop sepsis. Aside from antibiotics-based treatment of the causative infection and circulation-supportive measures, treatment options remain very limited. Better understanding of the immuno-pathophysiology of sepsis may lead to improved diagnostic and therapeutic solutions. Functional activity of the innate (inflammatory) and adaptive immune response is controlled by a dedicated set of cellular signal transduction pathways in the various immune cell types. To develop an immune response-based assay for sepsis for diagnostic, prognostic and therapeutic purposes, signaling pathway activities were analyzed in whole blood samples from patients with sepsis. Methods A prevalidated and previously published set of signal transduction pathway (STP) assays was used to analyze public Affymetrix expression microarray data from multiple clinical studies with pediatric and adult patients with sepsis. STP activity measurement is based on computational interpretation of a preselected set of target gene mRNA expression levels. STP assays were used to calculate androgen receptor, estrogen receptor, JAK-STAT1/2, JAK-STAT3, Notch, Hedgehog, TGFβ, FOXO-PI3K, MAPK-AP1, and NFκB signal transduction pathway activity scores for individual patient samples. Results Activity of both AR and TGFβ pathways was increased in both children and adults with sepsis. Using the upper threshold of normal pathway activity range as threshold diagnostic assay parameters were determined. For pediatric sepsis diagnosis, the AR pathway assay showed high sensitivity (77%) and specificity (97%), with a PPV of 99% and NPV of 50%. For prediction of favorable prognosis (survival), PPV was 95%, NPV was 21%. The TGFβ pathway activity assay performed slightly less for diagnosing sepsis, with a sensitivity of 64% and specificity of 98% (PPV 99%, NPV 39%) Conclusion We have demonstrated potential clinical use of measuring AR and TGFβ pathway activity in sepsis patients. Both androgen receptor and TGFβ pathways have been described as immunosuppressive pathways, and increased activity in patients with sepsis suggests a causal relation with the immunopathology in sepsis. The AR pathway assay has been converted to a qPCR test for further testing of clinical utility for sepsis diagnosis and prediction of prognosis, as well as for prediction of risk at developing sepsis in patients with a bacterial infection. In view of their putative role in sepsis pathophysiology, both the AR and TGFβ pathways may present novel drug targets in sepsis.

scholarly journals Potential role of transforming growth factor beta1 in drug resistance of tumor cells.

2003 ◽  
Vol 50 (2) ◽  
pp. 497-508 ◽  
Author(s):  
Rostyslav Stoika ◽  
Mariya Yakymovych ◽  
Serhiy Souchelnytskyi ◽  
Ihor Yakymovych
Keyword(s):  
Signal Transduction ◽  
Drug Resistance ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Signal Transduction Pathway ◽  
Target Cells ◽  
Type I ◽  
Transduction Pathway ◽  
L1210 Cells ◽  
Anti Cancer

Acquired drug resistance of tumor cells is frequently observed in cancer patients undergoing chemotherapy. We studied murine leukemia L1210 cells sensitive and resistant to the cytotoxic action of cisplatin and showed that cisplatin-resistant leukemia cells were also refractory to TGF beta1-dependent growth inhibition and apoptosis. Addressing the question about the mechanisms responsible for the cross-resistance to cisplatin and TGF beta1, we found that cisplatin- and TGF beta1-resistant L1210 cells possessed a decreased expression of type I TGF beta1 receptor, while the expression of type II TGF beta1 receptor was not affected. Western blot analysis of Smad proteins 2, 3, 4, 6, and 7, which participate in signal transduction pathway down-stream of the TGF beta1 receptors, revealed an increased expression of Smad 6, inhibiting TGF beta1 action, only in cisplatin- and TGF beta1-resistant L1210 cells. TGF beta1 and especially the cytotoxic mistletoe agglutinin increased Smad 6 expression in TGF beta1-sensitive but not in TGF beta1-resistant L1210 cells. TGF beta1-resistant L1210 cells also differed from TGF beta1-sensitive cells by the lack of expression of the pro-apoptotic p53 protein and higher level of expression of the anti-apoptotic Bcl-2 protein. Thus, the described co-expression of tumor cell refractoriness to an anti-cancer drug and to the inhibitory cytokine TGF beta1 is accompanied by multiple changes in the TGF beta1 signal transduction pathway and in other regulatory systems of the target cells. Besides, we found that various anti-tumor drugs and cytotoxic plant lectins increased the level of TGF beta1 expression in both TGFbeta1-sensitive and -resistant L1210 cells. A hypothesis is proposed that TGFbeta1 can at least partly mediate the effect of cell-stressing agents and, thus, the development of TGF beta1 resistance may be responsible for the appearance of tumor cell refractoriness to the action of some anti-cancer drugs.

scholarly journals Fatty acid-binding protein 5 (FABP5)-related signal transduction pathway in castration-resistant prostate cancer cells: a potential therapeutic target

2019 ◽  
Vol 2 (3) ◽  
pp. 192-196 ◽  
Author(s):  
Abdulghani A Naeem ◽  
Saud A Abdulsamad ◽  
Philip S Rudland ◽  
Mohammed I Malki ◽  
Youqiang Ke
Keyword(s):  
Prostate Cancer ◽  
Signal Transduction ◽  
Cancer Cells ◽  
Fatty Acid Binding Protein ◽  
Signal Transduction Pathway ◽  
Transduction Pathway ◽  
Castration Resistant Prostate Cancer ◽  
Fatty Acid Binding ◽  
Castration Resistant ◽  
Fold Reduction

Abstract In this short communication, a novel fatty acid-binding protein 5 (FABP5)-related signal transduction pathway in prostate cancer is reviewed. In castration-resistant prostate cancer (CRPC) cells, the FABP5-related signal transduction pathway plays an important role during transformation of the cancer cells from androgen-dependent state to androgen-independent state. The detailed route of this signal transduction pathway can be described as follows: when FABP5 expression is increased as the increasing malignancy, excessive amounts of fatty acids from intra- and extra-cellular sources are transported into the nucleus of the cancer cells where they act as signalling molecules to stimulate their nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ). The phosphorylated or biologically activated PPARγ then modulates the expression of its downstream target regulatory genes to trigger a series of molecular events that eventually lead to enhanced tumour expansion and aggressiveness caused by an overgrowth of the cancer cells with a reduced apoptosis and an increased angiogenesis. Suppressing the FABP5-related pathway via RNA interference against FABP5 has produced a 63-fold reduction in the average size of the tumours developed from CRPC cells in nude mice, a seven-fold reduction of tumour incidence, and a 100% reduction of metastasis rate. Experimental treatments of CRPC with novel FABP5 inhibitors have successfully inhibited the malignant progression of CRPC cells both in vitro and in nude mouse. These studies suggest that FABP5-related signal transduction pathway is a novel target for therapeutic intervention of CRPC cells.

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