Side-chain modified vitamin D analogs require activation of both PI 3-K and erk1,2 signal transduction pathways to induce differentiation of human promyelocytic leukemia cells.

• Authors: Ewa Marcinkowska , Andrzej Kutner
• Languages of publication: EN

Abstracts

EN

Synthetic analogs of vitamin D for potential use in differentiation therapy should selectively regulate genes necessary for differentiation without inducing any perturbations in calcium homeostasis. PRI-1906, an analog of vitamin D2, and PRI-2191, an analog of vitamin D3 bind nuclear vitamin D receptor (nVDR) with substantially lower affinity than 1,25-dihydroxyvitamin D3 (1,25-D3), but have higher differentiation-inducing activity as estimated in HL-60 leukemia cell model. To examine how their increased differentiation-inducing activity is regulated we tested the hypothesis that membrane-mediated events, unrelated to nVDR, take part in the differentiation in response to PRI-1906 and PRI-2191. The induction of leukemia cell differentiation in response to the analogs of vitamin D was inhibited by LY294002 (phosphatidylinositol 3-kinase inhibitor), PD98059 (inhibitor of MEK1,2, an upstream regulator of extracellular-signal regulated kinase) and rapamycin (p70S6K inhibitor) pointing out that activation of signal transduction pathways unrelated to nVDR is necessary for differentiation. On the other hand, inhibition of cytosolic phospholipase A2 accelerated the differentiation of HL-60 cells induced by either 1,25-D3 or by the vitamin D analogs suggesting possible existence of a feedback loop between extracellular-signal regulated kinases and phospholipase A2.

Keywords

EN

CD11b; cytosolic phospholipase A2; p70S6K; nuclear vitamin D receptor; CD14; analogs; phosphatidylinositol 3-kinase; extracellular-signal regulated kinase; 1,25-dihydroxyvitamin D3; HL-60 cells; differentiation

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2002
• Volume: 49
• Issue: 2
• Pages: 393-406

Dates

published

2002

received

2002-01-16

revised

2002-04-16

accepted

2002-05-21

Contributors

author

Ewa Marcinkowska

• Department of Reproductive Immunology, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland

author

Andrzej Kutner

• Pharmaceutical Research Institute, Warszawa, Poland

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