Inhibition of proliferation and induction of apoptosis in soft tissue sarcoma cells by interferon-α and retinoids

Brodowicz, Thomas; Wiltschke, Christoph; Kandioler-Eckersberger, Daniela; Grunt, Thomas W.; Rudas, Margaretha; Schneider, Sebastian; Hejna, Michael; Budinsky, Alexandra C.; Zielinski, C.

doi:10.1038/sj.bjc.6690528

Cited by 34 publications

(22 citation statements)

References 34 publications

(32 reference statements)

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“…Previous experiments demonstrated that treatment with AtRA resulted in significantly decreased growth versus ethanol-treated control cells (Crouch and Helman, 1991;Brodowicz et al, 1999). We confirmed this finding in our experiment.…”

Section: Discussionsupporting

confidence: 82%

“…However, as cell lines inherently have resistance to pharmacologic doses of therapeutic agents, this dose was deemed appropriate for our studies. Moreover, this dose has been previously established as one that effectively inhibits RMS growth in vitro (Crouch and Helman, 1991;Brodowicz et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…Retinoic acid has been previously shown to reduce VEGF production by various tumour types (Weninger et al, 1998;Kini et al, 2001) and slow RMS growth (Crouch and Helman, 1991;Brodowicz et al, 1999). We hypothesized, therefore, that VEGF production by RMS cells may be decreased with treatment by 5 mM AtRA, a dose that has previously been shown to arrest RMS cell growth (Crouch and Helman, 1991 at day 2, and at day 6, the percent rescue was 74% (Po0.001).…”

Section: Atra Decreases Vegf 165 Production By Rh4 Cellsmentioning

confidence: 99%

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Vascular endothelial growth factor acts in an autocrine manner in rhabdomyosarcoma cell lines and can be inhibited with all-trans-retinoic acid

et al. 2005

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Atra Decreases Vegf 165 Production By Rh4 Cellsmentioning

confidence: 99%

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Vascular endothelial growth factor acts in an autocrine manner in rhabdomyosarcoma cell lines and can be inhibited with all-trans-retinoic acid

et al. 2005

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“…This agent has potent effects against acute promyelocytic leukemia blast cells, and its introduction in the clinical management of the disease has dramatically changed the outcome of this historically fatal subtype of acute leukemia (5). RA and other retinoids have been shown to inhibit cell growth or to promote programmed cell death of neoplastic cells of diverse origin (7)(8)(9)(10)(11)(12)(13)(14). The molecular mechanisms that regulate the induction of the biological effects of retinoids include a series of signaling events that are initiated by the binding of retinoids to specific receptors in the nucleus of target cells.…”

Section: All-trans-retinoic Acid (Ra)mentioning

confidence: 99%

Activation of Protein Kinase Cδ by All-trans-retinoic Acid

Kambhampati

Verma

et al. 2003

Journal of Biological Chemistry

102

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All-trans-retinoic acid (RA) is a potent inhibitor of leukemia cell proliferation and induces differentiation of acute promyelocytic leukemia cells in vitro and in vivo.For RA to induce its biological effects in target cells, binding to specific retinoic acid nuclear receptors is required. The resulting complexes bind to RA-responsive elements (RAREs) in the promoters of RA-inducible genes to initiate gene transcription and to generate protein products that mediate the biological effects of RA. In this report, we provide evidence that a member of the protein kinase C (PKC) family of proteins, PKC␦, is activated during RA treatment of the NB-4 and HL-60 acute myeloid leukemia cell lines as well as the MCF-7 breast cancer cell line. Such RA-dependent phosphorylation was also observed in primary acute promyelocytic leukemia cells and resulted in activation of the kinase domain of PKC␦. In studies aimed at understanding the functional relevance of PKC␦ in the induction of RA responses, we found that pharmacological inhibition of PKC␦ (but not of other PKC isoforms) diminished RA-dependent gene transcription via RAREs. On the other hand, overexpression of a constitutively active form of the kinase strongly enhanced RA-dependent gene transcription via RAREs. Gel shift assays and chromatin immunoprecipitation studies demonstrated that PKC␦ associated with retinoic acid receptor-␣ and was present in an RA-inducible protein complex that bound to RAREs. Pharmacological inhibition of PKC␦ activity abrogated the induction of cell differentiation and growth inhibition of NB-4 blast cells, demonstrating that its function is required for such effects. Altogether, our data provide strong evidence that PKC␦ is activated in an RA-dependent manner and plays a critical role in the generation of the biological effects of RA in malignant cells.

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“…RA and other retinoids also induce antitumor effects by inhibiting cell growth or promoting programmed cell death of neoplastic cells of diverse cellular origin (5)(6)(7)(8)(9)(10)(11)(12). The important biological effects of RA have led to intense efforts to understand the mechanisms by which it generates its biological effects on malignant cells.…”

mentioning

confidence: 99%

Activation of Rac1 and the p38 Mitogen-activated Protein Kinase Pathway in Response to All-trans-retinoic Acid

Alsayed¹,

Uddin²,

Mahmud³

et al. 2001

Journal of Biological Chemistry

149

137

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Several signaling pathways are activated by all-transretinoic acid (RA) to mediate induction of differentiation and apoptosis of malignant cells. In the present study we provide evidence that the p38 MAP kinase pathway is activated in a RA-dependent manner in the NB-4, acute promyelocytic leukemia, and the MCF-7, breast carcinoma, cell lines. RA treatment of cells induces a time-and dose-dependent phosphorylation of p38, and such phosphorylation results in activation of its catalytic domain. p38 activation is not inducible by RA in a variant NB-4 cell line, NB-4.007/6, which is resistant to the effects of RA, suggesting a role for this pathway in the induction of RA responses. Our data also demonstrate that the small G-protein Rac1 is activated by RA and functions as an upstream regulator of p38 activation, whereas the MAPKAPK-2 serine kinase is a downstream effector for the RA-activated p38. To obtain information on the functional role of the Rac1/p38/MAPKAPK-2 pathway in RA signaling, the effects of pharmacological inhibition of p38 on RA-induced gene transcription and cell differentiation were determined. Our results indicate that treatment of cells with the SB203580 inhibitor does not inhibit RA-dependent gene transcription via retinoic acid response elements or induction of Stat1 protein expression. However, treatment with SB203580 or SB202190 strongly enhances RA-dependent induction of cell differentiation and RA-regulated growth inhibitory responses. Altogether, our findings demonstrate that the Rac1/p38 MAP kinase pathway is activated in a RA-dependent manner and exhibits negative regulatory effects on the induction of differentiation.

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Inhibition of proliferation and induction of apoptosis in soft tissue sarcoma cells by interferon-α and retinoids

Cited by 34 publications

References 34 publications

Vascular endothelial growth factor acts in an autocrine manner in rhabdomyosarcoma cell lines and can be inhibited with all-trans-retinoic acid

Vascular endothelial growth factor acts in an autocrine manner in rhabdomyosarcoma cell lines and can be inhibited with all-trans-retinoic acid

Activation of Protein Kinase Cδ by All-trans-retinoic Acid

Activation of Rac1 and the p38 Mitogen-activated Protein Kinase Pathway in Response to All-trans-retinoic Acid

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