Abstract |
Chronic myelogenous leukemia (CML) is caused by expression of the Bcr-Abl fusion protein in hematopoietic stem cells. The MUC1-C oncoprotein is expressed in CML blasts and stabilizes Bcr-Abl. The present studies demonstrate that treatment of KU812 and K562 CML cells with GO-201, a cell-penetrating peptide inhibitor of MUC1-C oligomerization, downregulates Bcr-Abl expression and inhibits cell growth. In concert with decreases in Bcr-Abl levels, KU812 and K562 cells responded to GO-201 with induction of a differentiated myeloid phenotype as evidenced by increased expression of CD11b, CD11c and CD14. The results also show that the GO-201-treated cells undergo a late apoptotic/necrotic response, consistent with induction of terminal differentiation. Primary CML blasts expressing MUC1 similarly responded to GO-201 with induction of a more differentiated phenotype and late apoptosis/ necrosis. In addition, treatment of KU812 xenografts in nude mice was associated with upregulation of CD11 and tumor regression. These findings indicate that CML blasts respond to targeting of the MUC1-C oncoprotein with induction of terminal differentiation.
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Authors | Li Yin, Rehan Ahmad, Michio Kosugi, Takeshi Kawano, David Avigan, Richard Stone, Surender Kharbanda, Donald Kufe |
Journal | Cancer biology & therapy
(Cancer Biol Ther)
Vol. 10
Issue 5
Pg. 483-91
(Sep 01 2010)
ISSN: 1555-8576 [Electronic] United States |
PMID | 20592495
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Comment)
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Chemical References |
- Antineoplastic Agents
- CD11 Antigens
- CD11b Antigen
- CD11c Antigen
- GO 201
- Lipopolysaccharide Receptors
- Mucin-1
- Peptides
- Fusion Proteins, bcr-abl
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Topics |
- Animals
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(genetics)
- CD11 Antigens
(analysis)
- CD11b Antigen
(analysis)
- CD11c Antigen
(analysis)
- Cell Differentiation
- Cell Line, Tumor
- Fusion Proteins, bcr-abl
(genetics, metabolism)
- Humans
- Immunoblotting
- K562 Cells
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
(drug therapy, genetics, metabolism, pathology)
- Lipopolysaccharide Receptors
- Mice
- Mice, Inbred BALB C
- Molecular Targeted Therapy
- Mucin-1
(chemistry, genetics, metabolism)
- Myelopoiesis
- Peptides
(pharmacology)
- Protein Multimerization
- Protein Transport
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