Involvement of p53 and Raf/MEK/ERK pathways in hematopoietic drug resistance

McCubrey, James A.; Abrams, Stephen L.; Ligresti, Giovanni; Misaghian, Negin; Wong, Ellis W.T.; Steelman, Linda S.; Bäsecke, Jörg; Troppmair, Jakob; Libra, Massimo; Nicoletti, Ferdinando; Molton, Sarah A; McMahon, Martin; Evangelisti, Camilla; Martelli, Alberto M.

doi:10.1038/leu.2008.207

Cited by 73 publications

(111 citation statements)

References 59 publications

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“…[31][32][33] No significant differences in their abilities to efflux these two the FL5.12 cell line (<10 -7 ), making it an attractive model to analyze the effects various genes have on signal transduction, apoptosis and chemotherapeutic drug resistance. 22 In the following studies, we sought to determine the effects of Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways on drug resistance and sensitivity to targeted therapy. In order to investigate potential roles, we transformed IL3-dependent FL5.12 cells to proliferate in response to activation of Raf-1 and Akt-1 by introducing conditional ∆Raf-1:AR and ∆Akt-1:ER* constructs into these hematopoietic cells.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously demonstrated the individual roles of Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades in drug resistance and cell cycle progression. 22,30,36 In this current study, we compared the roles of these pathways in drug resistance in hematopoietic cells where we can conditionally control the expression of the Raf/MEK/ERK and PI3K/PTEN/Akt/ mTOR pathways. Raf-1 was dominant in terms of promoting both growth and drug resistance when compared to Akt-1.…”

Section: Discussionmentioning

confidence: 99%

“…Signal transduction inhibitors which target the PI3K/PTEN/Akt/mTOR and Raf/MEK/ERK pathways may prove to enhance chemotherapy. 6,22,30,33,35,36,[38][39][40][41][42][43][44][45][46] Furthermore targeting of the bone marrow microenvironment and the cancer stem cells with combinations of these signal transduction inhibitors and chemotherapy may enhance cancer treatment. [32][33][34][35][36]47 There are also complicated interactions between p53 and PI3K/PTEN/Akt/mTOR, Raf/MEK/ ERK and other signaling and apoptotic pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations occur in many of these pathway elements leading to uncontrolled regulation and in some cases resistance to chemo-and radiotherapy. [4][5][6][21][22][23][24] However, the precise details regarding how these pathways interact to result in therapy resistance is not well elucidated and furthermore, which pathway dominates is not clear. Elucidation of the mechanisms of therapy resistance could enhance cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

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The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy

et al. 2010

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy

et al. 2010

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“…63 The role of ERK 1/2 in drug resistance is now firmly established. 64 In this connection, it is important to emphasize that ErPC3 synergizes in vitro with chemotherapeutic drugs commonly used for treating AML ErPC3-mediated cyotoxicity in AML AM Martelli et al patients. 18 ErPC3 has been studied in a phase I dose escalation trial at the University of Munich.…”

Section: Discussionmentioning

confidence: 99%

Erucylphosphohomocholine, the first intravenously applicable alkylphosphocholine, is cytotoxic to acute myelogenous leukemia cells through JNK- and PP2A-dependent mechanisms

et al. 2010

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Alkylphospholipids and alkylphosphocholines (APCs) are promising antitumor agents, which target the plasma membrane and affect multiple signal transduction networks. We investigated the therapeutic potential of erucylphosphohomocholine (ErPC3), the first intravenously applicable APC, in human acute myelogenous leukemia (AML) cells. ErPC3 was tested on AML cell lines, as well as AML primary cells. At short (6-12 h) incubation times, the drug blocked cells in G2/M phase of the cell cycle, whereas, at longer incubation times, it decreased survival and induced cell death by apoptosis. ErPC3 caused JNK 1/2 activation as well as ERK 1/2 dephosphorylation. Pharmacological inhibition of caspase-3 or a JNK 1/2 inhibitor peptide markedly reduced ErPC3 cytotoxicity. Protein phosphatase 2A downregulation by siRNA opposed ERK 1/2 dephosphorylation and blunted the cytotoxic effect of ErPC3. ErPC3 was cytotoxic to AML primary cells and reduced the clonogenic activity of CD34 þ leukemic cells. ErPC3 induced a significant apoptosis in the compartment (CD34 þ CD38 Low/Neg CD123 þ ) enriched in putative leukemia-initiating cells. This conclusion was supported by ErPC3 cytotoxicity on AML blasts showing high aldehyde dehydrogenase activity and on the side population of AML cell lines and blasts. These findings indicate that ErPC3 might be a promising therapeutic agent for the treatment of AML patients.

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Overexpression of Tpl2 is linked to imatinib resistance and activation of MEK‐ERK and NF‐κB pathways in a model of chronic myeloid leukemia

et al. 2018

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The introduction of tyrosine kinase inhibitors (TKI) has transformed chronic myeloid leukemia (CML) into a chronic disease with long‐term survival exceeding 85%. However, resistance of CML stem cells to TKI may contribute to the 50% relapse rate observed after TKI discontinuation in molecular remission. We previously described a model of resistance to imatinib mesylate (IM), in which K562 cells cultured in high concentrations of imatinib mesylate showed reduced Bcr‐Abl1 protein and activity levels while maintaining proliferative potential. Using quantitative phosphoproteomic analysis of these IM‐resistant cells, we have now identified significant upregulation of tumor progression locus (Tpl2), also known as cancer Osaka thyroid (COT1) kinase or Map3k8. Overexpression of Tpl2 in IM‐resistant cells was accompanied by elevated activities of Src family kinases (SFKs) and NF‐κB, MEK‐ERK signaling. CD34+ cells isolated from the bone marrow of patients with CML and exposed to IM in vitro showed increased MAP3K8 transcript levels. Dasatinib (SFK inhibitor), U0126 (MEK inhibitor), and PS‐1145 (IκB kinase (IKK) inhibitor) used in combination resulted in elimination of 65% of IM‐resistant cells and reduction in the colony‐forming capacity of CML CD34+ cells in methylcellulose assays by 80%. In addition, CML CD34+ cells cultured with the combination of inhibitors showed reduced MAP3K8 transcript levels. Overall, our data indicate that elevated Tpl2 protein and transcript levels are associated with resistance to IM and that combined inhibition of SFK, MEK, and NF‐κB signaling attenuates the survival of IM‐resistant CML cells and CML CD34+ cells. Therefore, combination of SFK, MEK, and NF‐κB inhibitors may offer a new therapeutic approach to overcome TKI resistance in CML patients.

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Involvement of p53 and Raf/MEK/ERK pathways in hematopoietic drug resistance

Cited by 73 publications

References 59 publications

The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy

The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy

Erucylphosphohomocholine, the first intravenously applicable alkylphosphocholine, is cytotoxic to acute myelogenous leukemia cells through JNK- and PP2A-dependent mechanisms

Overexpression of Tpl2 is linked to imatinib resistance and activation of MEK‐ERK and NF‐κB pathways in a model of chronic myeloid leukemia

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