An enhanced anti-apoptotic capacity of tumor cells takes on an important part in the process of breakpoint cluster region/Abelson tyrosine kinase gene (BCR/ABL)-indie imatinib resistance. Like BCL-2 BEX1 was UKp68 localized to the mitochondria. The region between 33K and 64Q on BEX1 is definitely important for its localization to the mitochondria and GSK1070916 its ability to interact with BCL-2. Additionally we found that this region is essential for BEX1-controlled imatinib-induced apoptosis. Furthermore we shown that the connection between BCL-2 and BEX1 promotes imatinib-induced apoptosis by suppressing the formation of anti-apoptotic BCL-2/BCL-2-connected X protein (BAX) heterodimers. Our results revealed an connection between GSK1070916 BEX1 and BCL-2 and a novel mechanism of imatinib resistance mediated GSK1070916 from the BEX1/BCL-2 pathway. Intro Targeted inhibition of tyrosine kinases with imatinib (imatinib mesylate) is now a front collection therapy for individuals with chronic myelogenous leukemia (CML) or gastrointestinal stromal tumors (GISTs). However nearly 33% of GSK1070916 all CML individuals and 50% of all GISTs patients display disease progression during imatinib therapy due to the development of secondary resistance [1] [2]. Several mechanisms have been proposed to account for this resistance including breakpoint cluster region/Abelson tyrosine kinase gene (BCR/ABL)-dependent or BCR/ABL-independent mechanisms [2] [3]. BCR/ABL-dependent resistance mechanisms involve BCR/ABL mutations which alter the binding affinity of imatinib to the BCR/ABL tyrosine kinase and amplification which leads to improved expression of the GSK1070916 BCR/ABL kinase [4] [5]. BCR/ABL-independent resistance mechanisms include processes that affect drug delivery [5] [6]. Additionally enhanced suppression of apoptosis in tumor cells takes on an important part in the process of BCR/ABL-independent imatinib resistance [7]. Burchert et al. showed that activation of the anti-apoptotic PI3K/AKT/mTOR pathway happens during the early stages of imatinib resistance and inhibiting PI3K/AKT activation clogged the development of imatinib resistance [8]. Activation of the JAK-2/STAT-5 pathway and alterations in P53 were also reported in imatinib-resistant CML individuals [9] [10]. Tumor cells acquire resistance to apoptosis through numerous mechanisms that interfere at different phases of apoptosis signaling. One mechanism of resistance is the over-expression of anti-apoptotic genes. In both and models B-cell lymphoma 2 (BCL-2) manifestation confers resistance to many types of chemotherapeutic medicines [11] [12] [13]. Besides over-expression of anti-apoptotic genes tumors can acquire apoptosis resistance by downregulating or genetically altering pro-apoptotic molecules. For instance inhibition of BCL-2 interacting mediator (BIM) manifestation by RNAi can inhibit the killing effect of imatinib on GISTs cells and BCR/ABL+ tumor cells [14] [15]. In our earlier study we founded an imatinib-resistant K562 cell collection (KR) by gradually increasing the dose of imatinib in the tradition medium [16]. Interestingly resistance to imatinib in the KR cells is definitely through a BCR/ABL-independent manner. BCR/ABL mRNA and protein manifestation in KR cells was not significantly improved compared to the unique K562 cells and no mutation was found in the exons of the BCR/ABL locus. When analyzing the gene manifestation profile of KR cells we discovered that the human brain indicated X-linked 1 (BEX1) gene which is definitely involved in apoptosis was silenced. Re-expression of BEX1 in KR cells restored drug level of sensitivity by inducing apoptosis. BEX1 belongs to a family of six genes with a wide cells distribution in the body including the mind pancreas testis and ovary [17] [18]. Little is known about the function of the BEX1 protein which is only 128 amino acids long. Foltz et al. reported that BEX1 was silenced in malignant gliomas as a result of considerable promoter hypermethylation [19]. Furthermore re-expression of BEX1 resulted in a significant suppression of tumor growth and apoptosis induction in response to camptothecin treatment. GSK1070916 Here to better understand the part of BEX1 in imatinib-induced apoptosis we wanted to identify BEX1-interacting proteins using a candida two-hybrid display. The cDNA library used for this screen originated from imatinib-resistant K562 cells that overexpress BEX1 to overcome the imatinib resistance. BCL-2 was consequently identified as a potential.