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Role of peroxisome proliferator-activated receptor-gamma in hematologic malignancies
Marina Konopleva1, Michael Andreeff
1Department of Blood and Marrow Transplantation, Section of Molecular Hematology and Therapy, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Abstract:
Members of the nuclear receptor superfamily, including retinoic acid receptors (RARs), retinoid X receptors (RXRs), and vitamin D receptors (VDRs), are transcription factors that control many important cellular functions, and their ligands are widely used in several clinical indications. The latest family member is the peroxisome proliferator-activated receptor-gamma (PPARgamma), which is highly expressed in normal monocytes, different leukemias, and epithelial malignancies. PPARgamma ligands have been developed and signal differentiation, growth arrest, and apoptosis. PPARgamma forms heterodimers with RXR, and ligation of both receptors is required for maximal signaling. PPARgamma signaling, its expression in hematologic malignancies, and role in differentiation are discussed. Interactions of PPARgamma with X-RARalpha, protein kinase R (PKR), PTEN, and mitogen-activated protein kinase (MAPK) have been described. PPARgamma ligands have been developed for the management of diabetes, but new and more potent ligands, including triterpenoids, are being investigated as therapeutic agents for epithelial and hematologic malignancies.
Insights
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a key transcription factor in monocytes and malignancies. PPARgamma ligands show potential as therapeutic agents for various cancers.
Area of Science:
- Molecular Biology
- Cellular Biology
- Oncology
Background:
- Nuclear receptors, including retinoic acid receptors (RARs), retinoid X receptors (RXRs), and vitamin D receptors (VDRs), are crucial transcription factors regulating cellular functions.
- Peroxisome proliferator-activated receptor-gamma (PPARgamma), a recent addition to this superfamily, is notably expressed in monocytes, leukemias, and epithelial cancers.
Purpose of the Study:
- To discuss the role of PPARgamma signaling in hematologic malignancies and its function in cellular differentiation.
- To explore the interactions of PPARgamma with other key proteins like RXR, RARalpha, protein kinase R (PKR), PTEN, and mitogen-activated protein kinase (MAPK).
Main Methods:
- Literature review and discussion of existing research on PPARgamma signaling pathways.
- Analysis of PPARgamma expression patterns in various cancer types, particularly hematologic malignancies.
- Examination of the mechanism of action of PPARgamma ligands, including their role in inducing differentiation, growth arrest, and apoptosis.
Main Results:
- PPARgamma forms heterodimers with RXR, necessitating ligation of both for optimal signaling.
- PPARgamma signaling is implicated in the differentiation of monocytes and plays a role in controlling the growth of leukemias and epithelial malignancies.
- Interactions with PKR, PTEN, and MAPK pathways modulate PPARgamma activity.
Conclusions:
- PPARgamma is a significant therapeutic target in hematologic and epithelial malignancies.
- Novel PPARgamma ligands, such as triterpenoids, are being investigated for their enhanced potency and potential in cancer treatment.
- Understanding PPARgamma's role in differentiation and its interactions with other signaling molecules is crucial for developing effective cancer therapies.