Latest Publications

@article{valcikova_eif4f_2024,

title = {eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations.},

author = {Barbora Valcikova and Natalia Vadovicova and Karolina Smolkova and Magdalena Zacpalova and Pavel Krejci and Shannon Lee and Jens Rauch and Walter Kolch and Alexander Kriegsheim and Anna Dorotikova and Zdenek Andrysik and Rachel Vichova and Ondrej Vacek and Karel Soucek and Stjepan Uldrijan},

doi = {10.1073/pnas.2321305121},

issn = {1091-6490 0027-8424},

year  = {2024},

date = {2024-10-01},

journal = {Proceedings of the National Academy of Sciences of the United States of America},

volume = {121},

number = {44},

pages = {e2321305121},

abstract = {The eIF4F translation initiation complex plays a critical role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a function of eIF4F in the negative regulation of the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essential for controlling ERK signaling intensity in treatment-naïve melanoma cells harboring BRAF or NRAS mutations. Specifically, the dual-specificity phosphatase DUSP6/MKP3, which acts as a negative feedback regulator of ERK activity, requires continuous production in an eIF4F-dependent manner to limit excessive ERK signaling driven by oncogenic RAF/RAS mutations. Treatment with small-molecule eIF4F inhibitors disrupts the negative feedback control of MAPK signaling, leading to ERK hyperactivation and EGR1 overexpression in melanoma cells in vitro and in vivo. Furthermore, our quantitative analyses reveal a high spare signaling capacity in the ERK pathway, suggesting that eIF4F-dependent feedback keeps the majority of ERK molecules inactive under normal conditions. Overall, our findings highlight the crucial role of eIF4F in regulating ERK signaling flux and suggest that pharmacological eIF4F inhibitors can disrupt the negative feedback control of MAPK activity in melanomas with BRAF and NRAS activating mutations.},

note = {Place: United States},

keywords = {*Eukaryotic Initiation Factor-4F/metabolism/genetics, *GTP Phosphohydrolases/metabolism/genetics, *MAP Kinase Signaling System/genetics, *Melanoma/genetics/metabolism/pathology, *Membrane Proteins/metabolism/genetics, *Mutation, *Proto-Oncogene Proteins B-raf/genetics/metabolism, Animals, Cell Line, Dual Specificity Phosphatase 6/metabolism/genetics, DUSP6, eIF4F, ERK, Extracellular Signal-Regulated MAP Kinases/metabolism, Humans, MAP kinase, Melanoma, Mice, Tumor},

pubstate = {published},

tppubtype = {article}

}

@article{lincova_multiple_2009,

title = {Multiple defects in negative regulation of the PKB/Akt pathway sensitise human cancer cells to the antiproliferative effect of non-steroidal anti-inflammatory drugs.},

author = {Eva Lincová and Ales Hampl and Zuzana Pernicová and Andrea Starsíchová and Pavel Krcmár and Miroslav Machala and Alois Kozubík and Karel Soucek},

doi = {10.1016/j.bcp.2009.05.001},

issn = {1873-2968 0006-2952},

year  = {2009},

date = {2009-09-01},

journal = {Biochemical pharmacology},

volume = {78},

number = {6},

pages = {561–572},

abstract = {Antitumorigenic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are well established in several types of cancer disease. However, the mechanisms driving these processes are not understood in all details. In our study, we observed significant differences in sensitivity of cancer epithelial cell lines to COX-independent antiproliferative effects of NSAIDs. The prostate cancer cell line LNCaP, lacking both critical enzymes in the negative control of PKB/Akt activation, PTEN and SHIP2, was the most sensitive to these effects, as assessed by analysing the cell cycle profile and expression of cell cycle regulating proteins. We found that p53 protein and its signalling pathway is not involved in early antiproliferative action of the selected NSAID-indomethacin. RNAi provided evidence for the involvement of p21(Cip1/Waf1), but not GDF-15, in antiproliferative effects of indomethacin in LNCaP cells. Interestingly, we also found that indomethacin activated PKB/Akt and induced nuclear localisation of p21(Cip1/Waf1) and Akt2 isoform. Our results are in agreement with other studies and suggest that maintaining of the p21(Cip1/Waf1) level and its intracellular localisation might be influenced by Akt2. Knock-down of SHIP2 by RNAi in PTEN negative prostate and colon cancer cell lines resulted in higher sensitivity to antiproliferative effects of indomethacin. Our data suggest novel mechanisms of NSAIDs antiproliferative action in cancer epithelial cells, which depends on the status of negative regulation of the PKB/Akt pathway and the isoform-specific action of Akt2. Thus, unexpectedly, multiple defects in negative regulation of the PKB/Akt pathway may contribute to increased sensitivity to chemopreventive effects of these widely used drugs.},

note = {Place: England},

keywords = {Anti-Inflammatory Agents, Antineoplastic Agents/pharmacology, Cell Cycle Proteins/metabolism, Cell Cycle/*drug effects/physiology, Cell Line, Cyclin-Dependent Kinase Inhibitor p21/*biosynthesis, Enzyme Induction, Epithelial Cells/*drug effects/pathology, Extracellular Signal-Regulated MAP Kinases/metabolism, Gene Expression/drug effects, Growth Differentiation Factor 15/biosynthesis, Humans, Indomethacin/pharmacology, Male, Non-Steroidal/*pharmacology, Phosphatidylinositol 3-Kinases, Prostatic Neoplasms/*pathology, Proto-Oncogene Proteins c-akt/*metabolism, RNA Interference, Signal Transduction/drug effects/physiology, Tumor, Tumor Suppressor Protein p53/genetics/*metabolism},

pubstate = {published},

tppubtype = {article}

}