Journal
ONCOTARGET
Volume 8, Issue 42, Pages 72652-72665Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.20194
Keywords
Ubenimex; hepatocellular carcinoma; multi-drug resistance; CD13; Pim-3 kinase
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Funding
- Natural Science Foundation of Shandong Province, China [ZR2011HQ032]
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Hepatocellular carcinoma (HCC) is one of the most serious cancers, with rapid progression and high mortality. However, chemotherapy of HCC is hindered by multi-drug resistance (MDR). It is urgent, therefore, to explore new approaches for overcoming MDR of HCC cells. Ubenimex, an inhibitor of CD13, has been used as an immuno-enhancer for treating hematological neoplasms and other solid tumors. Here, we demonstrate that Ubenimex can also reverse MDR in the HCC cell lines HepG2/5FU and Bel7402/5-FU. Ubenimex inhibits the expression of the proto-oncogene, Pim-3, which is accompanied by decreased expression of BCL-2 and BCL-XL, decreased phosphorylation of Bad, and increased tumor apoptosis. Moreover, Ubenimex decreases expression of the MDR-associated proteins P-gp, MRP3 and MRP2 to enhance intracellular accumulation of Cisplatin, for which downregulation of Pim-3 is essential. Our results reveal a previously uncharacterized function of Ubenimex in mediating drug resistance in HCC, which suggests that Ubenimex may provide a new strategy to reverse MDR and improve HCC sensitivity to chemotherapeutic drugs via its effects on Pim-3.
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