Programmed Cell Death-4 Tumor Suppressor Protein Contributes to Retinoic Acid–Induced Terminal Granulocytic Differentiation of Human Myeloid Leukemia Cells

Özpolat, Bülent; Akar, Uğur; Steiner, Michael; Zorrilla-Calancha, Isabel; Tírado-Gómez, Maribel; Colburn, Nancy H.; Danilenko, Michael; Kornblau, Steven M.; Berestein, Gabriel Lopez

doi:10.1158/1541-7786.mcr-06-0125

Cited by 87 publications

(73 citation statements)

References 64 publications

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“…35,36 We have recently identified RTP801, the stress responsive gene, as one of the all-trans-RA -target genes responsive to all-trans-RA -mediated differentiation of AML cells. RTP801 is a negative regulator of the mTOR pathway.…”

Section: Discussionmentioning

confidence: 99%

Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells

et al. 2008

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This study found that MS-275, a novel synthetic benzamide histone deacetylase inhibitor (HDACI), blocked Akt/mammalian target of rapamycin (mTOR) signaling in acute myelogenous leukemia (AML) HL60 and acute promyelocytic leukemia (APL) NB4 cells, as assessed by decreased levels of the phosphorylated (p)-Akt, p-p70 ribosomal S6 kinase (p70S6K) and p-S6K by western blot analysis. Interestingly, further inactivation of mTOR by rapamycin analog RAD001 (everolimus) significantly enhanced MS-275-mediated growth inhibition and apoptosis of these cells in parallel with enhanced upregulation of p27 kip1 and downregulation of c-Myc. In addition, RAD001 potentiated the ability of MS-275 to induce differentiation of HL60 and NB4 cells, as measured by the expression of CD11b cell surface antigens, as well as reduction of nitroblue tetrazolium. Importantly, RAD001 potentiated the ability of MS-275 to induce the expression of the myeloid differentiation-related transcription factor, CCAAT enhancer-binding protein-e, in these cells in association with enhanced acetylation of histone H3 on its promoter. Furthermore, RAD001 (5 mg/kg) significantly enhanced the effects of MS-275 (10 mg/kg) to inhibit proliferation of HL60 tumor xenografts in nude mice without adverse effects. Taken together, concomitant administration of an HDACI and an mTOR inhibitor may be a promising treatment strategy for the individuals with a subset of human leukemia.

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Section: Discussionmentioning

confidence: 99%

Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells

et al. 2008

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“…It should be noted that PDCD4 is expressed in normal tissues, whereas there is evidence that its expression is suppressed in various tumors (69 -74), including lung cancer (71), breast cancer (72), hepatocellular carcinoma (73), and gliomas (74). Such suppressed expression may have important consequences in tumorigenesis and neoplastic transformation, since there is accumulating evidence that PDCD4 promotes apoptosis and cell differentiation of neoplastic cells (72)(73)(74)(75), whereas it also blocks AP-1 activation, malignant transformation, and neoplastic cell invasion in different systems (15, 76 -78).…”

Section: Discussionmentioning

confidence: 99%

Suppression of Programmed Cell Death 4 (PDCD4) Protein Expression by BCR-ABL-regulated Engagement of the mTOR/p70 S6 Kinase Pathway

Carayol

Katsoulidis

Sassano

et al. 2008

Journal of Biological Chemistry

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There is accumulating evidence that mammalian target of rapamycin (mTOR)-activated pathways play important roles in cell growth and survival of BCR-ABL-transformed cells. We have previously shown that the mTOR/p70 S6 kinase (p70 S6K) pathway is constitutively activated in BCR-ABL transformed cells and that inhibition of BCR-ABL kinase activity by imatinib mesylate abrogates such activation. We now provide evidence for the existence of a novel regulatory mechanism by which BCR-ABL promotes cell proliferation, involving p70 S6K-mediated suppression of expression of programmed cell death 4 (PDCD4), a tumor suppressor protein that acts as an inhibitor of cap-dependent translation by blocking the translation initiation factor eIF4A. Our data also establish that second generation BCR-ABL kinase inhibitors block activation of p70 S6K and downstream engagement of the S6 ribosomal protein in BCR-ABL transformed cells. Moreover, PDCD4 protein expression is up-regulated by inhibition of the BCR-ABL kinase in K562 cells and BaF3/BCR-ABL transfectants, suggesting a mechanism for the generation of the proapoptotic effects of such inhibitors. Knockdown of PDCD4 expression results in reversal of the suppressive effects of nilotinib and imatinib mesylate on leukemic progenitor colony formation, suggesting an important role for this protein in the generation of antileukemic responses. Altogether, our studies identify a novel mechanism by which BCR-ABL may promote leukemic cell growth, involving sequential engagement of the mTOR/p70 S6K pathway and downstream suppression of PDCD4 expression. Chronic myeloid leukemia (CML)2 is a clonal myeloproliferative disorder, whose hallmark is the presence of the BCR-ABL oncoprotein, which results from the abnormal bcr-abl fusion oncogene (1-3). bcr-abl is created by a reciprocal translocation involving chromosomes 9 and 22, and its abnormal protein product plays a key and essential role in the pathogenesis of CML (1-4). The constitutive tyrosine kinase activity of BCR-ABL mediates phosphorylation of multiple downstream substrates and engagement of various mitogenic pathways that promote cell growth and survival (1-7). The introduction of imatinib mesylate in the management of chronic myelogenous leukemia has had a dramatic impact on the natural history of the disease (reviewed in Refs. 8 -11). This agent induces long lasting hematologic and cytogenetic responses in patients with early and late phase CML (8, 12, 13, 14, 16 -18) by its ability to block activation the BCR-ABL kinase and generation of mitogenic responses (8 -11).Although the introduction of imatinib mesylate was a major breakthrough in the management of CML, there has been emerging evidence for resistance to its antileukemic properties in vitro and in vivo (19 -22). Such resistance involves a variety of cellular mechanisms, including mutations of the bcr-abl gene, amplification of the bcr-abl gene locus, and activation of downstream signaling elements, such as Src-kinase-dependent pathways (19,(23)(24)(25)(26)(27)(28). Research ...

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“…The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway has been shown to induce the proteolysis of PDCD4 [31] and reduce the transcription of PDCD4 [32]. MicroRNA-21 has been reported to block PDCD4 expression transcriptionally [33] and post-transcriptionally [34].…”

Section: Pdcd4 Increases Timp-2 Expression To Inhibit Breast Cancer Imentioning

confidence: 99%

Programmed Cell Death 4 inhibits breast cancer cell invasion by increasing Tissue Inhibitor of Metalloproteinases-2 expression

Nieves-Alicea

Colburn

Simeone

et al. 2008

Breast Cancer Res Treat

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High levels of the cyclooxygenase-2 (COX-2) protein have been associated with invasion and metastasis of breast tumors. Both prostaglandin E 2 (PGE 2 ) and interleukin-8 (IL-8) have been shown to mediate the invasive activity of COX-2 in breast cancer cells. Here we expand these studies to determine how COX-2 uses PGE 2 and IL-8 to induce breast cancer cell invasion. We demonstrated that PGE 2 and IL-8 decreased the expression of the tumor suppressor protein Programmed Cell Death 4 (PDCD4). We hypothesized that suppression of PDCD4 expression is vital to the invasive activity of PGE 2 and IL-8. In MCF-7 cells overexpressing PDCD4 (MCF-7/PDCD4), PGE 2 and IL-8 failed to induce invasion, in contrast to the parental MCF-7 cells, thus indicating that PDCD4 blocks breast cancer cell invasion. MCF-7/PDCD4 cells produced higher levels of the Tissue Inhibitor of Metalloproteinases-2 (TIMP-2) than the parental cells. Silencing TIMP-2 mRNA in MCF-7/PDCD4 cells reversed the anti-invasive effects of PDCD4, allowing PGE 2 and IL-8 to induce the invasion of these cells. Here we report the novel findings that suppression of PDCD4 expression is vital for the invasive activity of COX-2 mediated by PGE 2 and IL-8, and that PDCD4 increases TIMP-2 expression to inhibit breast cancer cell invasion.

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Programmed Cell Death-4 Tumor Suppressor Protein Contributes to Retinoic Acid–Induced Terminal Granulocytic Differentiation of Human Myeloid Leukemia Cells

Cited by 87 publications

References 64 publications

Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells

Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells

Suppression of Programmed Cell Death 4 (PDCD4) Protein Expression by BCR-ABL-regulated Engagement of the mTOR/p70 S6 Kinase Pathway

Programmed Cell Death 4 inhibits breast cancer cell invasion by increasing Tissue Inhibitor of Metalloproteinases-2 expression

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