Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10801767 | Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | 2016 | 10 Pages |
Abstract
Galectin 3 (LGALS3) expression is prognostic for poor survival in acute myeloid leukemia (AML) patients. GCS-100 is a novel galectin inhibitor that may prove useful for AML therapy. In this study, we found that GCS-100 induced apoptosis in AML cells. The agent reduced MCL-1 expression suggesting that GCS-100 could be more effective when combined with a BH3 mimetic. Indeed, potent synergistic cytotoxicity was achieved when GCS-100 was combined with ABT-737 or ABT-199. Furthermore, the GCS-100/ABT-199 combination was effective against primary AML blast cells from patients with FLT3 ITD mutations, which is another prognostic factor for poor outcome in AML. This activity may involve wild-type p53 as shRNA knockdown of LGALS3 or galectin 1 (LGALS1) sensitized wild-type p53 OCI-AML3 cells to GCS-100/ABT-737-induced apoptosis to a much greater extent than p53 null THP-1 cells. Suppression of LGALS3 by shRNA inhibited MCL-1 expression in OCI-AML3 cells, but not THP-1 cells, suggesting the induced sensitivity to ABT-737 may involve a MCL-1 mediated mechanism. OCI-AML3 cells with LGALS1 shRNA were also sensitized to ABT-737. However, these cells exhibited increased MCL-1 expression, so MCL-1 reduction is apparently not required in this process. A role for p53 appears important as GCS-100 induces p53 expression and shRNA knockdown of p53 protected OCI-AML3 cells from the cytotoxic effects of the GCS-100/ABT-737 treatment combination. Our results suggest that galectins regulate a survival axis in AML cells, which may be targeted via combined inhibition with drugs such as GCS-100 and ABT-199.
Keywords
LGALS3AMLFANCD2TET1p53Mcl-1ERKqRT-PCRGCN2GSK3NPM1Bcl2Bcl-xLReal-time PCRAktB cell lymphoma 2leukemiaacute myeloid leukemiaMyeloid cell leukemia 1Acute lymphoblastic leukemiaNucleophosmin 1Signal transductionprotein kinase Bgeneral control nonderepressible 2extracellular receptor kinasegalectingalectin 1galectin 3glycogen synthase kinase 3
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Authors
Peter P. Ruvolo, Vivian R. Ruvolo, Christopher B. Benton, Ahmed AlRawi, Jared K. Burks, Wendy Schober, James Rolke, George Tidmarsh, Numsen Jr, R. Eric Davis, Michael Andreeff,