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Idelalisib Promotes Bim-Dependent Apoptosis Through AKT/Foxo3a in Hepatocellular Carcinoma Dan Yue1 and Xun Sun2

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Idelalisib Promotes Bim-Dependent Apoptosis Through AKT/Foxo3a in Hepatocellular Carcinoma Dan Yue1 and Xun Sun2 Yue and Sun Cell Death and Disease (2018) 9:935 DOI 10.1038/s41419-018-0960-8 Cell Death & Disease ARTICLE Open Access Idelalisib promotes Bim-dependent apoptosis through AKT/FoxO3a in hepatocellular carcinoma Dan Yue1 and Xun Sun2 Abstract Idelalisib, a selective PI3Kδ inhibitor, has been approved by the FDA for chronic lymphocytic leukemia/small lymphocytic lymphoma treatment and for follicular lymphoma treatment when combined with rituximab. However, the mechanisms of effective action of idelalisib in hepatocellular carcinoma (HCC) remain unclear. In the current study, we aimed to investigate how idelalisib inhibits the growth of HCC cells and enhances the effects of other chemotherapeutic drugs. Our results show that idelalisib treatment promotes Bim induction in HCC via the FoxO3a pathway following PI3K/AKT inactivation. Moreover, our results show that Bim is required for idelalisib-mediated apoptosis in HCC. Idelalisib also synergizes with sorafenib or doxorubicin to induce significant apoptosis in HCC, and Bim is also necessary for the induction of apoptosis by cotreatment. Furthermore, a xenograft experiment reveals that the Bim deficiency abolishes apoptosis and antitumor effects of idelalisib in vivo. In summary, our results indicate a key role of Bim in mediating the antitumor effects of idelalisib in HCC. Our results also support the clinical significance of the drug. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction cytosolic tyrosine kinase participating in various signaling Hepatocellular carcinoma (HCC) represents the pathways in B-cells6,7. Idelalisib is approved by FDA as second leading cause of cancer-related deaths worldwide, monotherapy, or in combination with rituximab (Rituxan, especially in developing countries1,2. The incidence of for the treatment of small lymphocytic lymphoma, HCC in developed countries is on the rise due to recurrent chronic lymphocytic leukemia (CLL) and folli- the progress of hepatitis C viral (HCV) infection in the cular lymphoma8. However, idelalisib has side effects, elderly, as well as to alcohol consumption, the prevalence such as colitis, diarrhea, severe hepatotoxicity, and of obesity and the nonalcoholic fatty liver disease related intestinal perforation9,10. Idelalisib has also been found to to the metabolic syndrome2,3. Over the past few decades, be effective in p53-mutated CLL patients with high-risk the treatment of HCC has undergone significant changes, genetic traits, which suggests the treatment of p53 dele- such as an introduction of liver transplantation, liver tion/mutant patients should involve screening for idela- resection, systemic therapy and hepatic artery-targeted lisib11,12. However, the mechanism of autonomous effects chemotherapy4,5. of idelalisib, such as cell killing in solid tumors, is unclear. Idelalisib (CAL-101 or GS-1101) belongs to a class of Apoptosis, a process of programmed cell death, occurs inhibitors of phosphatidylinositol 3 kinase delta (PI3Kδ), a in multicellular organisms and is regulated by both proapoptotic and anti-apoptotic proteins13,14. The proa- poptotic protein Bim (Bcl2L11) is a Bcl-2 family member Correspondence: Dan Yue ([email protected]) and has three major isoforms (Bim- , Bim- , and Bim- ), 1 EL L S Department of Laboratory Medicine, Shengjing Hospital of China Medical which can be produced by alternative mRNA splicing15. University, Shenyang, China 2Department of Immunology, China Medical University, Shenyang, China Together with other proapoptotic proteins, such as Bad, Edited by M. Agostini © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Yue and Sun Cell Death and Disease (2018) 9:935 Page 2 of 11 Bax, PUMA, and anti-apoptotic proteins, such as Bcl-2, was slowly added to the cells. Medium containing Bcl-XL, and Mcl-1, Bim regulates the homeostasis that is lentiviral particles was obtained after 2 days of transfec- essential for normal cell death and survival15,16. Precise tion. For lentivirus infection, 6-well plates were seeded regulation of Bim expression has been shown to be with HepG2 cells (4–5×104 per well). The infected cells essential for normal development17. Decreasing Bim were selected with puromycin at a concentration of expression can disrupt tumor suppression, accelerate 2 µg/mL after 1 day of infection and then incubated at 18,19 tumorigenesis, and induce autoimmunity . 37 °C and 5% CO2. For selecting a single clone, the sur- In the current study, our results indicate that idelalisib viving cells were seeded on a 96-well plate. Western induces Bim activation via the AKT/FoxO3a pathway, blotting was used to confirm the knockout cells. which plays a key role in therapeutic response to idelalisib in HCC. MTS assay Indicated cell lines were seeded in 96-well plates at a Materials and Methods density of 1 × 104 cells/well. After overnight incubation, Cell culture and drug treatment various concentrations of idelalisib were added into wells The HCC cell lines, Hep G2, Hep3B, SNU-398, PLHC-1 and incubated for additional 72 h. The 3-(4,5-dimethyl- and embryonic kidney 293T cells were obtained from thiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophe- American Type Culture Collection (ATCC, Manassas, nyl)-2H-tetrazolium (MTS) assay was performed using VA, USA). HuH-7 cell line was got from Japanese Col- the MTS assay kit (Promega, Durham, NC, USA) lection of Research Bioresources (JCRB), normal hepato- according to the manufacturer’s instructions. Lumines- cyte cell line HL-7702 was got from Institute of cence was measured with a Wallac Victor 1420 Multilabel Biochemistry and Cell Biology (SIBS, CAS, Shanghai, Counter (Perkin Elmer, Akron, OH, USA). Each assay was China). All HCC cells were cultured in DMEM medium conducted in triplicate and repeated three times. supplemented with 10% fetal bovine serum (FBS), 100 µg/ mL streptomycin and 100 units/mL penicillin (Invitrogen, RNA extraction and real-time reverse transcriptase (RT) Carlsbad, CA, USA). The drugs, including idelalisib, sor- PCR afenib, doxorubicin (Selleckchem, Houston, TX, USA), Total RNA was extracted using the TRIzol RNA Kit were diluted with DMSO. Constitutively active AKT was (Invitrogen, Carlsbad, USA) according to the manu- obtained from Addgene (Cambridge, MA, USA). facturer’s protocol. One µg of total RNA was used to generate cDNA using SuperScript II reverse transcriptase CRISPR-Cas9-mediated Bim Knockout (Invitrogen, Carlsbad, USA). PCR was performed in tri- To generate Bim knockout cells, two gRNA sequences plicate using SsoFasrTM Probes Supermix (Bio-Rad) in a targeting Bim were selected (5′-GACAATTGCAGC final reaction volume of 20 μL with gene-specific primer/ CTGCGGAG-3′;5′-GCCCAAGAGTTGCGGCGTAT- probe sets, and a standard thermal cycling procedure (35 3′). Single-stranded complementary oligos with BsmBI cycles) in a Bio-Rad CFX96TM real-time PCR system. Bim overhangs were generated. The LentiCRISPR v2 lentiviral and β-actin levels were assessed using TaqMan Gene vector (Addgene, Cambridge, MA, USA) was digested Expression Real-Time PCR assays. The results were using FastDigest BsmBI obtained from Fermentas. The expressed as the threshold cycles (Ct). The relative digested product was purified using the QIAquick Gel quantification of the target transcripts was determined by Extraction Kit (Qiagen, Germantown, MD, USA), fol- the comparative Ct method (ΔΔCt) according to the −ΔΔ lowed by elution in EB buffer. Phosphorylation as well as manufacturer’s protocol. The 2 Ct method was used to annealing of the oligos was carried out using T4 poly- analyze the relative changes in gene expression. Control nucleotide kinase in T4 ligation Buffer (NEB, Ipswich, experiments were conducted without reverse transcrip- MA, USA). The reaction was incubated at 37 °C for tion to confirm that the total RNA was not contaminated 30 min, followed by 90 °C for 5 min, and finally cooled to with genomic DNA. β-actin was used as an internal 25 °C at a rate of 5 °C/min. The ligation reaction was control gene for normalization. carried out by mixing the oligos to be annealed, the digested LentiCRISPR v2 vector, and the Quick Ligase Western blotting enzyme included in the Quick Ligase Buffer, before Proteins were extracted and western blotting was per- transformation into Stbl3 bacteria. Human 293T cells formed as described previously20, with antibodies against (2 × 106) were seeded on tissue culture plates (60 mm) 24 AKT (9272, 1:1000), phospho-AKT (5012, 1:1000), Bid h prior to transfection. Subsequently, 1 µg of lentiviral (2002, 1:2000), cleaved-caspase 3 (9661, 1:1000), cleaved- products was mixed with pMD2G and psPAX plasmids, caspase 9 (9505, 1:1000), phospho-FoxO3a (9466, 1:1000), as well as the PolyJet agent in serum-free media. After Bak (6947, 1:1000), FoxO3a (2497, 1:1000), cytochrome 15-min incubation at room temperature, the mixture oxidase subunit IV (Cox IV) (4850, 1:2000) (Cell Signaling Official journal of the Cell Death Differentiation Association Yue and Sun Cell Death and Disease (2018) 9:935 Page 3 of 11 Technology, Beverly, CA, USA), E2F1 (sc-193, 1:1000), tumors reached ~1.0 cm3 in size. Tumors were dissected Egr-1 (sc-110, 1:1000), cytochrome c (sc-8385, 1:1000), β- and fixed in 10% formalin and embedded in paraffin.
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