Targeting mcl-1 for radiosensitization of pancreatic cancers.
In order to identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer, we previously conducted an RNAi library screen of 8,800 genes. We identified Mcl-1 (myeloid cell leukemia-1), an anti-apoptotic member of the Bcl-2 family, as a target for sensitizing pancreatic cancer cells to chemoradiation. In the present study we investigated Mcl-1 inhibition by either genetic or pharmacological approaches as a radiosensitizing strategy in pancreatic cancer cells. Mcl-1 depletion by siRNA produced significant radiosensitization in BxPC-3 and Panc-1 cells in association with Caspase-3 activation and PARP cleavage, but only minimal radiosensitization in MiaPaCa-2 cells. We next tested the ability of the recently identified, selective, small molecule inhibitor of Mcl-1, UMI77, to radiosensitize in pancreatic cancer cells. UMI77 caused dissociation of Mcl-1 from the pro-apoptotic protein Bak and produced significant radiosensitization in BxPC-3 and Panc-1 cells, but minimal radiosensitization in MiaPaCa-2 cells. Radiosensitization by UMI77 was associated with Caspase-3 activation and PARP cleavage. Importantly, UMI77 did not radiosensitize normal small intestinal cells. In contrast, ABT-737, an established inhibitor of Bcl-2, Bcl-XL, and Bcl-w, failed to radiosensitize pancreatic cancer cells suggesting the unique importance of Mcl-1 relative to other Bcl-2 family members to radiation survival in pancreatic cancer cells. Taken together, these results validate Mcl-1 as a target for radiosensitization of pancreatic cancer cells and demonstrate the ability of small molecules which bind the canonical BH3 groove of Mcl-1, causing displacement of Mcl-1 from Bak, to selectively radiosensitize pancreatic cancer cells.
Department of Radiation Oncology, University of Michigan Medical School.
Dongping
D
Wei
Department of Radiation Oncology, University of Michigan Medical School.
Qiang
Q
Zhang
Department of Radiation Oncology, University of Michigan Medical School.
Jason S
JS
Schreiber
Department of Pharmacology, University of Michigan Medical School.
Leslie A
LA
Parsels
Department of Pathology, University of Michigan Medical School.
Fardokht A
FA
Abulwerdi
Department of Radiation Oncology, University of Michigan Medical School.
Tasneem
T
Kausar
Department of Radiation Oncology, University of Michigan Medical School.
Theodore S
TS
Lawrence
Department of Radiation Oncology, University of Michigan Medical School.
Yi
Y
Sun
Department of Pathology, University of Michigan Medical School.
Zaneta
Z
Nikolovska-Coleska
Department of Radiation Oncology, University of Michigan Medical School. Electronic address: mmccrack@med.umich.edu.
Meredith A
MA
Morgan