scholarly journals Acquired resistance to zoledronic acid and the parallel acquisition of an aggressive phenotype are mediated by p38-MAP kinase activation in prostate cancer cells

2013 ◽  
Vol 4 (5) ◽  
pp. e641-e641 ◽  
Author(s):  
M R Milone ◽  
B Pucci ◽  
F Bruzzese ◽  
C Carbone ◽  
G Piro ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Zoledronic Acid ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Critical Role ◽  
Resistance Index ◽  
P38 Map Kinase ◽  
Cross Resistance ◽  
Mesenchymal Transition ◽  
P38 Mapk Pathway

Abstract The nitrogen-containing bisphosphonates (N-BP) zoledronic acid (ZOL) inhibits osteoclast-mediated bone resorption, and it is used to prevent skeletal complications from bone metastases. ZOL has also demonstrated anticancer activities in preclinical models and, recently, in cancer patients, highlighting the interest in determining eventual mechanisms of resistance against this agent. In our study, we selected and characterised a resistant subline of prostate cancer (PCa) cells to better understand the mechanisms, by which tumour cells can escape the antitumour effect of ZOL. DU145R80-resistant cells were selected in about 5 months using stepwise increasing concentrations of ZOL from DU145 parental cells. DU145R80 cells showed a resistance index value of 5.5 and cross-resistance to another N-BP, pamidronate, but not to the non-nitrogen containing BP clodronate. Notably, compared with DU145 parental cells, DU145R80 developed resistance to apoptosis and anoikis, as well as overexpressed the anti-apoptotic protein Bcl-2 and oncoprotein c-Myc. Moreover, DU145R80 cells underwent epithelial to mesenchymal transition (EMT) and showed increased expression of the metalloproteases MMP-2/9, as well as increased invading capability. Interestingly, compared with DU145, DU145R80 cells also increased the gene expression and protein secretion of VEGF and the cytokines Eotaxin-1 and IL-12. At the molecular level, DU145R80 cells showed strong activation of the p38-MAPK-dependent survival pathway compared with parental sensitive cells. Moreover, using the p38-inhibitor SB203580, we completely reversed the resistance to ZOL, as well as EMT marker expression and invasion. Furthermore, SB203580 treatment reduced the expression of VEGF, Eotaxin-1, IL-12, MMP-9, Bcl-2 and c-Myc. Thus, for the first time, we demonstrate that the p38-MAPK pathway can be activated under continuous extensive exposure to ZOL in PCa cells and that the p38-MAPK pathway has a critical role in the induction of resistance, as well as in the acquisition of a more aggressive and invasive phenotype.

scholarly journals Activin Inhibits the Human Pit-1 Gene Promoter through the p38 Kinase Pathway in a Smad-Independent Manner

Endocrinology ◽  
2006 ◽  
Vol 147 (9) ◽  
pp. 4351-4362 ◽  
Author(s):  
Chantal de Guise ◽  
Annie Lacerte ◽  
Shahrzad Rafiei ◽  
Rachel Reynaud ◽  
Melanie Roy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pituitary Gland ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Critical Role ◽  
Gene Promoter ◽  
Negative Regulator ◽  
P38 Kinase ◽  
P38 Mapk Pathway ◽  
Lactotrope Cells

The pituitary transcription factor Pit-1 regulates hormonal production from the anterior pituitary gland. However, the mechanisms by which Pit-1 gene expression is regulated in humans are poorly understood. Activin, a member of the TGFβ superfamily, acts as a negative regulator of cell growth and prolactin gene expression in lactotrope cells. In this study, we show that activin negatively regulates the human Pit-1 gene promoter. We defined a 117-bp element within the Pit-1 promoter that is sufficient to relay these inhibitory effects. We further investigated the signaling pathways that mediate activin-induced inhibition of Pit-1 gene promoter in pituitary lactotrope cells. We found that the activin effects on Pit-1 gene regulation are Smad independent and require the p38 MAPK pathway. Specifically, blocking p38 kinase activity reverses activin-mediated inhibition of the Pit-1 gene promoter. Together, our results highlight the p38 MAPK pathway as a key regulator of activin function in pituitary lactotrope cells and further emphasizes the critical role played by activin in regulating hormonal production in the pituitary gland.

Activation of TAO2 Kinase by Arsenic Trioxide in Leukemic Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5324-5324
Author(s):  
Jennifer L. McNeer ◽  
Blazej Dolniak ◽  
Barbara Kroczynska ◽  
Antonella Sassano ◽  
Leonidas Platanias
Keyword(s):  
Arsenic Trioxide ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Leukemic Cell ◽  
Buthionine Sulfoximine ◽  
P38 Map Kinase ◽  
Leukemic Cells ◽  
Kinase Assay ◽  
P38 Mapk Pathway

Abstract Arsenic Trioxide (As2O3) has major efficacy in the treatment of acute promyelocytic leukemia (APL), but its use in other malignancies is limited by the need for high intracellular concentrations to induce apoptosis. Prior work in our laboratory has demonstrated that the p38 MAP kinase (MAPK) pathway is activated following treatment of cells with As2O3 and exhibits negative regulatory effects on As2O3-induced apoptosis and growth suppression. In the current study, we sought to identify upstream effector mechanisms by which the p38 pathway is activated by As2O3 in leukemic cells. We found that the MAPK kinase kinase TAO2 (thousand and one amino acid protein kinase 2) is phosphorylated on Ser181 after treatment of NB4, NB4.306, and U937 cells with arsenic. Such phosphorylation was rapid, occurring as early as after 5 minutes of As2O3 treatment. In addition, our data indicate that such phosphorylation occurs downstream of As2O3-induced redox reactions, as demonstrated by increased phosphorylation in cells pretreated with the oxidizing agent buthionine sulfoximine (BSO) and decreased phosphorylation following pretreatment with the reducing agent dithiothreitol (DTT). Arsenic treatment of the cells also resulted in activation of the kinase domain of TAO2, as evidenced in in vitro kinase assay studies using ATF2 as an exogenous substrate. siRNA-mediated TAO2 knockdown resulted in inhibition of As2O3-induced p38 phosphorylation, suggesting that this kinase acts as an upstream effector of the arsenic-activated p38 MAPK pathway. Moreover, in studies to determine the functional relevance of TAO2 in the induction of As2O3-dependent antileukemic responses we found that siRNA-mediated TAO2 knockdown enhanced the suppressive effects of As2O3 on KT1-derived leukemic progenitor (CFU-L) growth in clonogenic assays in methylcellulose. Altogether, our data demonstrate that TAO2 is activated during arsenic treatment of leukemic cells lines and acts as an upstream activator of the p38 MAPK pathway. Such activation appears to occur in a negative feedback regulatory manner to compensate for the suppressive effects of As2O3 on leukemic cell growth. Importantly, these findings raise the possibility that targeting TAO2 may provide a novel approach to enhance the generation of the antileukemic properties of As2O3.

scholarly journals Diabetes mellitus stimulates pancreatic cancer growth and epithelial-mesenchymal transition-mediated metastasis via a p38 MAPK pathway

Oncotarget ◽  
2016 ◽  
Vol 7 (25) ◽  
pp. 38539-38550 ◽  
Author(s):  
Lishan Wang ◽  
Ying-Ying Bai ◽  
Yang Yang ◽  
Fangfang Hu ◽  
Yonghui Wang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Pancreatic Cancer ◽  
P38 Mapk ◽  
Epithelial Mesenchymal Transition ◽  
Mapk Pathway ◽  
Cancer Growth ◽  
Mesenchymal Transition ◽  
P38 Mapk Pathway

scholarly journals The SEK-1 p38 MAP kinase pathway modulates Gq signaling in C. elegans

2016 ◽  
Author(s):  
Jill M. Hoyt ◽  
Samuel K. Wilson ◽  
Madhuri Kasa ◽  
Jeremy S. Rise ◽  
Irini Topalidou ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Mapk Pathway ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Positive Role ◽  
C Elegans ◽  
Downstream Target ◽  
P38 Mapk Pathway ◽  
Mitogen Activated Protein ◽  
Mature Neurons

AbstractGq is a heterotrimeric G protein that is widely expressed in neurons and regulates neuronal activity. To identify pathways regulating neuronal Gq signaling we performed a forward genetic screen in Caenorhabditis elegans for suppressors of activated Gq. One of the suppressors is an allele of sek-1, which encodes a mitogen-activated protein kinase kinase (MAPKK) in the p38 MAPK pathway. Here we show that sek-1 mutants have a slow locomotion rate and that sek-1 acts in acetylcholine neurons to modulate both locomotion rate and Gq signaling. Furthermore, we find that sek-1 acts in mature neurons to modulate locomotion. Using genetic and behavioral approaches we demonstrate that other components of the p38 MAPK pathway also play a positive role in modulating locomotion and Gq signaling. Finally, we find that mutants in the SEK-1 p38 MAPK pathway partially suppress an activated mutant of the sodium leak channel NCA-1/NALCN, a downstream target of Gq signaling. Our results suggest that the SEK-1 p38 pathway may modulate the output of Gq signaling through NCA-1.

Role of the p38 MAPK Pathway in Induction of iNOS Expression in Human Leukocytes

2008 ◽  
Vol 56 (1) ◽  
pp. 83-89 ◽  
Author(s):  
Ewa Jablonska ◽  
Wioletta Ratajczak ◽  
Jakub Jablonski
Keyword(s):  
P38 Mapk ◽  
Mapk Pathway ◽  
Inos Expression ◽  
Human Leukocytes ◽  
P38 Mapk Pathway
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