Preclinical study of MEK1/2 inhibitor AZD6244 combined with gemcitabine for treatment of biliary cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 240-240
Author(s):  
Junyao Xu ◽  
Jennifer J. Knox ◽  
Ming Sound Tsao ◽  
Eric Xueyu Chen ◽  
Pinjiang Cao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Preclinical Study ◽  
Erk Signaling ◽  
Therapeutic Effects ◽  
Biliary Cancer

240 Background: MEK1/2 is an integral component of the Ras/Raf/MEK/ERK signaling pathway, implicated in uncontrolled cell proliferation and cell survival, a key hallmark of cancer. AZD6244, a novel inhibitor of MEK1/2, is currently completing Phase II clinical trials in biliary cancer, with modest antitumor activity observed as monotherapy. Gemcitabine is a cytotoxic drug commonly used in biliary cancer therapy but many patients showed early resistance. In this preclinical study, we investigated the sequence-dependent antitumor effects of AZD6244 combined with gemcitabine in biliary cancer models. Methods: Two biliary cancer cell lines (EGI-1 and TFK-1) were used. In vitro the effects of single drug or three combination protocols(concurrently; AZD6244 followed by GEM or Gem followed by AZD6244) on cell proliferation, DNA synthesis, and cell cycle distribution were evaluated by MTS, clonogenic assay, EdU uptake and flow cytometry. Drug interactions were analyzed by Chou-Talaly method. In vivo, 4 tumor models subcutaneously xenografted in SCID mice from the two cell lines and 2 human patients were set up to compare the therapeutic effects of different sequence-scheduled combinations. Results: AZD6244 caused G1-S cell cycle arrest in biliary cancer cells in vitro and in vivo, and this effect is correlated with the MEK/ERK signaling pathway blocking. Synchronized progression of the population through S phase were observed in 15h after removal of AZD6244 in cell culture or 48h after final dose of acute AZD6244 treatment in vivo. Antagonistic or additive effects was observed in vitro when combination were given as concurrently(CI=2.03~2.46) or Gem followed by AZD6244(CI=1.34~1.78). In contrast, a synergistic antiproliferative activity was obtained when AZD6244 was given first followed by a drug-free interval before Gem treatment (CI=0.53~0.69). In vivo, the best therapeutic effects were obtained with the sequence of AZD6244 followed by Gem, compared with concurrent or reverse sequence. Conclusions: This study provides a sound rationale for a Phase II trial of a potentially synergistic sequence of MEK inhibitor AZD6244 followed by gemcitabine in patients with advanced biliary cancer.

SRPK1 promotes cell proliferation and tumor growth of osteosarcoma through activation of the NF-κB signaling pathway

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Yubao Gong ◽  
Chen Yang ◽  
Zhengren Wei ◽  
Jianguo Liu
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Expression Level ◽  
Osteosarcoma Cell ◽  
Human Osteosarcoma

Abstract To explore the expression and the functions of SRPK1 in osteosarcoma, we retrieved transcription profiling dataset by array of human bone specimens from patients with osteosarcoma from ArrayExpress (accession E-MEXP-3628) and from Gene Expression Omnibus (accession GSE16102) and analyzed expression level of SRPK1 and prognostic value in human osteosarcoma. Then we examined the effect of differential SRPK1 expression levels on the progression of osteosarcoma, including cell proliferation, cell cycle, apoptosis, and investigated its underlying molecular mechanism using in vitro osteosarcoma cell lines and in vivo nude mouse xenograft models. High expression level of SRPK1 was found in human osteosarcoma tissues and cell lines as compared to the normal bone tissues and osteoblast cells, and predicted poor prognosis of human osteosarcoma. Overexpression of SRPK1 in osteosarcoma U2OS cells led to cell proliferation but inhibition of apoptosis. In contrast, knockdown of SRPK1 in HOS cells impeded cell viability and induction of apoptosis. Moreover, silencing SRPK1 inhibited osteosarcoma tumor growth in nude mice. Mechanistic studies revealed that SRPK1 promoted cell cycle transition in osteosarcoma cells and activation of NF-κB is required for SRPK1 expression and its pro-survival signaling. SRPK1 promoted human osteosarcoma cell proliferation and tumor growth by regulating NF-κB signaling pathway.

scholarly journals Tanshinone IIA Inhibits Osteosarcoma Growth through a Src Kinase-Dependent Mechanism

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Chao Hu ◽  
Xiaobin Zhu ◽  
Taogen Zhang ◽  
Zhouming Deng ◽  
Yuanlong Xie ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Src Kinase ◽  
Akt Signaling ◽  
Cellular Level ◽  
Tanshinone Iia

Introduction. Osteosarcoma is a malignant tumor associated with high mortality rates due to the toxic side effects of current therapeutic methods. Tanshinone IIA can inhibit cell proliferation and promote apoptosis in vitro, but the exact mechanism is still unknown. The aims of this study are to explore the antiosteosarcoma effect of tanshinone IIA via Src kinase and demonstrate the mechanism of this effect. Materials and Methods. Osteosarcoma MG-63 and U2-OS cell lines were stable transfections with Src-shRNA. Then, the antiosteosarcoma effect of tanshinone IIA was tested in vitro. The protein expression levels of Src, p-Src, p-ERK1/2, and p-AKt were detected by Western blot and RT-PCR. CCK-8 assay and BrdU immunofluorescence assay were used to detect cell proliferation. Transwell assay, cell scratch assay, and flow cytometry were used to detect cell invasion, migration, and cell cycle. Tumor-bearing nude mice with osteosarcoma were constructed. The effect of tanshinone IIA was detected by tumor HE staining, tumor inhibition rate, incidence of lung metastasis, and X-ray. Results. The oncogene role of Src kinase in osteosarcoma is reflected in promoting cell proliferation, invasion, and migration and in inhibiting apoptosis. However, Src has different effects on cell proliferation, apoptosis, and cell cycle regulation among cell lines. At a cellular level, the antiosteosarcoma effect of tanshinone IIA is mediated by Src downstream of the MAPK/ERK and PI3K/AKt signaling pathways. At the animal level, tanshinone IIA played a role in resisting osteosarcoma formation by Src downstream of the MAPK/ERK and PI3K/AKt signaling pathways. Conclusion. Tanshinone IIA plays an antiosteosarcoma role in vitro and in vivo and inhibits the progression of osteosarcoma mediated by Src downstream of the MAPK/ERK and PI3K/AKt signaling pathways.

scholarly journals Pharmacologic Inhibition of DYRK1A Results in Hyperactivation and Hyperphosphorylation of MYC and ERK Rendering KMT2A-R ALL Cells Sensitive to BCL2 Inhibition

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 506-506
Author(s):  
Christian Hurtz ◽  
Gerald Wertheim ◽  
John Chukinas ◽  
Joseph Patrick Loftus ◽  
Sung June Lee ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
B Cell ◽  
Cell Lines ◽  
Research Funding ◽  
Crispr Screen ◽  
Cycle Regulation ◽  
Pharmacologic Inhibition

Abstract Background: KMT2A-rearranged (R) ALL is a high-risk disease with a frequency of 75% in infants and 10% in children and adults with ALL and is associated with chemoresistance, relapse, and poor survival. Current intensive multiagent chemotherapy regimens induce significant side effects, yet fail to cure many patients, demonstrating continued need for novel therapeutic approaches. We performed a kinome-wide CRISPR screen and identified that DYRK1A is specifically required for the survival of KMT2A-R ALL cell. DYRK1A is a member of the dual-specificity tyrosine phosphorylation-regulated kinase family and has been reported as negatively regulator of cell proliferation. Results: We performed a kinome-wide CRISPR screen in human ALL cell lines and PDX models and identified DYRK1A as a novel target in KMT2A-R ALL. DYRK1A is a serine-threonine kinase with a proposed, but poorly defined role in cell cycle regulation. We performed a meta-analysis of multiple ChIP-Seq experiments and identified that oncogenic KMT2A fusions directly bind to the DYRK1A promoter. Our RT-PCR and Western blot analyses of KMT2A-R ALL cells treated with a menin inhibitor (MI-503) to disrupt the transcriptional activity of the KMT2A-R complex resulted in the downregulation of DYRK1A, indicating that DYRK1A is directly regulated by the KMT2A fusion complex. We further observed that pharmacologic inhibition of DYRK1A with EHT1610 induced potent leukemic cell growth inhibition in vitro and in vivo, demonstrating that DYRK1A could be a new therapeutic target in KMT2A-R ALL cells. To further elucidate the mechanism of DYRK1A function, we treated several KMT2A-R ALL cell lines in vitro with EHT1610, which surprisingly resulted in the upregulation of MYC and hyperphosphorylation of the RAS/MAPK target ERK. Given that ERK hyperactivation stops B cell proliferation during early B cell development to allow them to rearrange their B cell receptor, we hypothesized that cell cycle inhibition upon ERK hyperactivation remains as a conserved mechanism of cell cycle regulation in KMT2A-R ALL. Strikingly, combining DYRK1A inhibition with the MEK inhibitor trametinib antagonistically rescued KMT2A-R ALL cell proliferation, indicating that ERK hyperactivation is the main driver of DYRK1A inhibitor mediated cell cycle arrest. Given that DYRK1A inhibitor does not induce apoptosis and cells restart cell proliferation after EHT1610 withdrawal we concluded that a DYRK1A monotherapy may not be an ideal new treatment option. However, it has been reported that increased MYC activity induces the accumulation of BIM in Burkitt's Lymphoma. Given the increased expression of MYC following DYRK1A inhibition we performed a new Western blot analysis and validated increased expression of BIM in our KMT2A-R ALL cell lines after EHT1610 treatment. To test if targeting the interaction of BIM with BCL2 will induce an apoptotic effect when combined with EHT1610, we treated four KMT2A-R ALL cell lines with increasing concentrations of EHT1610 and the BCL2 inhibitor venetoclax. Strikingly, the combination of DYRK1A inhibition with BCL2 inhibition synergistically killed KMT2A-R ALL cells. Conclusion: Our results validate DYRK1A as an important molecule to regulate cell proliferation via inhibition of MYC and ERK. Targeting DYRK1A results in the accumulation of BIM, which renders the cells sensitive to BCL2 inhibition via venetoclax. While further in vivo studies are needed, we predict that combining DYRK1A inhibition with venetoclax may be a novel precision medicine strategy for the treatment of KMT2A-R ALL. Figure 1 Figure 1. Disclosures Crispino: Forma Therapeutics: Research Funding; Scholar Rock: Research Funding; MPN Research Foundation: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy. Tasian: Aleta Biotherapeutics: Consultancy; Gilead Sciences: Research Funding; Kura Oncology: Consultancy; Incyte Corporation: Research Funding. Carroll: Incyte Pharmaceuticals: Research Funding; Janssen Pharmaceutical: Consultancy.

GDF11 impairs liver regeneration in mice after partial hepatectomy

2019 ◽  
Vol 133 (20) ◽  
pp. 2069-2084
Author(s):  
Wenjie Wang ◽  
Xiao Yang ◽  
Jiankun Yang ◽  
Shenpei Liu ◽  
Yongman Lv ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Liver Regeneration ◽  
Signaling Pathway ◽  
Partial Hepatectomy ◽  
Neutralizing Antibodies ◽  
Cell Cycle Progression ◽  
Transforming Growth Factor

Abstract Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor (TGF)-β superfamily. The rejuvenative effect of GDF11 has been called into question recently, and its role in liver regeneration is unclear. Here, we investigated the pathophysiologic role of GDF11, as well as its plausible signaling mechanisms in a mouse model of partial hepatectomy (PH). We demonstrated that both serum and hepatic GDF11 protein expression increased following PH. Treatment with adeno-associated viruses-GDF11 and recombinant GDF11 protein severely impaired liver regeneration, whereas inhibition of GDF11 activity with neutralizing antibodies significantly improved liver regeneration after PH. In vitro, GDF11 treatment significantly delayed cell proliferation and induced cell-cycle arrest in α mouse liver 12 (AML12) cells. Moreover, GDF11 activated TGF-β-SMAD2/3 signaling pathway. Inhibition of GDF11-induced SMAD2/3 activity significantly blocked GDF11-mediated reduction in cell proliferation both in vivo and in vitro. In the clinical setting, GDF11 levels were significantly elevated in patients after hepatectomy. Collectively, these results indicate that rather than a ‘rejuvenating’ agent, GDF11 impairs liver regeneration after PH. Suppression of cell-cycle progression via TGF-β-SMAD2/3 signaling pathway may be a key mechanism by which GDF11 inhibits liver regeneration.

scholarly journals Activin B Stimulates Mouse Vibrissae Growth and Regulates Cell Proliferation and Cell Cycle Progression of Hair Matrix Cells through ERK Signaling

2019 ◽  
Vol 20 (4) ◽  
pp. 853
Author(s):  
Pei Tang ◽  
Xueer Wang ◽  
Min Zhang ◽  
Simin Huang ◽  
Chuxi Lin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Cell Cycle Progression ◽  
Erk Signaling ◽  
Follicle Growth ◽  
Cycle Progression ◽  
Matrix Cell ◽  
Hair Matrix

Activins and their receptors play important roles in the control of hair follicle morphogenesis, but their role in vibrissae follicle growth remains unclear. To investigate the effect of Activin B on vibrissae follicles, the anagen induction assay and an in vitro vibrissae culture system were constructed. Hematoxylin and eosin staining were performed to determine the hair cycle stages. The 5-ethynyl-2′-deoxyuridine (EdU) and Cell Counting Kit-8 (CCK-8) assays were used to examine the cell proliferation. Flow cytometry was used to detect the cell cycle phase. Inhibitors and Western blot analysis were used to investigate the signaling pathway induced by Activin B. As a result, we found that the vibrissae follicle growth was accelerated by 10 ng/mL Activin B in the anagen induction assay and in an organ culture model. 10 ng/mL Activin B promoted hair matrix cell proliferation in vivo and in vitro. Moreover, Activin B modulates hair matrix cell growth through the ERK–Elk1 signaling pathway, and Activin B accelerates hair matrix cell transition from the G1/G0 phase to the S phase through the ERK–Cyclin D1 signaling pathway. Taken together, these results demonstrated that Activin B may promote mouse vibrissae growth by stimulating hair matrix cell proliferation and cell cycle progression through ERK signaling.

scholarly journals SCUBE3 Downregulation Modulates Hepatocellular Carcinoma By Inhibiting CCNE1 Via TGFβ/PI3K/AKT/GSK3β Pathway

2021 ◽  
Author(s):  
Pan xu ◽  
Aoran Luo ◽  
Chuan Xiong ◽  
Hong Ren ◽  
Yan Liang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Akt Signaling ◽  
Cell Counting ◽  
Pathway Enrichment Analysis ◽  
Akt Signaling Pathway

Abstract Objectives: We aimed to verify the role of signal peptide-CUB-EGF-like domain-containing protein3 (SCUBE3) in the hepatocellular carcinoma (HCC) progression.Methods: The role·of SCUBE3 in HCC cell proliferation, apoptosis, and cell cycle in vitro were investigated using MTT assay, 5-ethynyl-2´-deoxyuridine assay (EDU), Celigo cell counting assay, Caspase3/7 activity assay, and flow cytometry. The effect of SCUBE3 on HCC cell proliferation in vivo was investigated by a xenograft tumor model in nude mice. The related mechanisms were further investigated.Results: SCUBE3 was upregulated in HCC tissues and cell lines. Knockdown of SCUBE3 inhibited proliferation, promoted apoptosis, and induced cell cycle arrest in HCC cell lines in vitro and vivo. Screening of cell cycle-related proteins revealed CCNL2, CDK6, CCNE1, and CCND1 exhibited a significantly different expression profile. We found that SCUBE3 may promote the proliferation of HCC cells by regulating CCNE1 expression. The pathway enrichment analysis showed that the TGFβ signaling pathway and the PI3K/AKT signaling pathway were significantly altered. Co-immunoprecipitation results showed that SCUBE3 binds to the TGFβRII receptor. SCUBE3 knockdown inhibited the PI3K/AKT signaling pathway and the phosphorylation of GSK3β to inhibit its kinase activity.Conclusions：SCUBE3 promotes HCC development by regulating CCNE1 via TGFβ/PI3K/AKT/GSK3βpathway. In addition, SCUBE3 may be a new molecular target for clinical diagnosis and treatment of HCC.

scholarly journals Lenvatinib Inhibits Intrahepatic Cholangiocarcinoma Growth via Gadd45a-Mediated Cell Cycle Arrest

2021 ◽  
Author(s):  
Xia Yan ◽  
Dan Wang ◽  
Liping Zhuang ◽  
Peng Wang ◽  
Zhiqiang Meng ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Intrahepatic Cholangiocarcinoma ◽  
Primary Liver Cancer ◽  
Transcriptional Profiling ◽  
Cycle Arrest

Abstract Background: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer, and its 5-year survival rate is less than 10%. Fibroblast growth factor receptor (FGFR) changes have been observed in 6%-50% of ICC patients, and patients with FGFR mutations have been shown to have more inert tumour biological activity than patients with wild-type FGFRs. Thus, as a pan-FGFR inhibitor, lenvatinib is supposed to play an anti-tumour role in ICC. However, no relevant experiments have been reported.Methods: Patients derived xenograft (PDX) model and cell line derived xenograft (CDX) model were both used for the in vivo study. For in vivo work, ICC cell lines were applied to analyse the effect of Lenvatinib on cell proliferation, cell cycle progression, apoptosis, and the molecular mechanism.Reaults: In the present study, we found that lenvatinib dramatically hindered in vivo tumor growth in ICC patient-derived xenograft models. In addition, by using in vitro experiments in ICC cell lines, we found that lenvatinib dose- and time-dependently inhibited the proliferation of ICC cells and induced cell cycle arrest in the G0/G1 phase. Transcriptional profiling analysis further applied indicated that lenvatinib might inhibit cell proliferation through the induction of cell-cycle arrestment via activating of Gadd45a, it was evidenced by that the knockout of Gadd45a significantly attenuated the cycle arrest induced by lenvatinib, as well as the inhibitory effect of lenvatinib on ICC.Conclusion: Our work firstly found that lenvatinib exerted excellent antitumor effect on ICC, mainly via inducing Gadd45a mediated cell cycle arrest. Our work provides evidence and a rationale for the future use of lenvatinib in the treatment of ICC.

scholarly journals SCUBE3 downregulation modulates hepatocellular carcinoma by inhibiting CCNE1 via TGFβ/PI3K/AKT/GSK3β pathway

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Pan Xu ◽  
Aoran Luo ◽  
Chuan Xiong ◽  
Hong Ren ◽  
Liang Yan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Signalling Pathway ◽  
Cell Counting ◽  
Pathway Enrichment Analysis

Abstract Objectives We aimed to verify the role of signal peptide-CUB-EGF-like domain-containing protein3 (SCUBE3) in the hepatocellular carcinoma (HCC) progression. Methods The role of SCUBE3 in HCC cell proliferation, apoptosis, and cell cycle in vitro were detected using MTT assay, colony formation assay, 5-ethynyl-2´-deoxyuridine assay (EDU), Celigo cell counting assay, Caspase3/7 activity assay, and flow cytometry. The effect of SCUBE3 on HCC cell proliferation in vivo was inspected by a xenograft tumour model in nude mice. The related mechanisms were further studied. Results The level of SCUBE3 was upregulated in HCC tissues and cell lines. Knockdown of SCUBE3 inhibited proliferation, promoted apoptosis, and induced cell cycle arrest in HCC cell lines in vitro and in vivo. Screening of cell cycle-related proteins revealed that CCNL2, CDK6, CCNE1, and CCND1 exhibited a significantly different expression profile. We found that SCUBE3 may promote the proliferation of HCC cells by regulating CCNE1 expression. The pathway enrichment analysis showed that the TGFβ signalling pathway and the PI3K/AKT signalling pathway were significantly altered. Co-immunoprecipitation results showed that SCUBE3 binds to the TGFβRII receptor. SCUBE3 knockdown inhibited the PI3K/AKT signalling pathway and the phosphorylation of GSK3β to inhibit its kinase activity. Conclusions SCUBE3 promotes HCC development by regulating CCNE1 via TGFβ/PI3K/AKT/GSK3β pathway. In addition, SCUBE3 may be a new molecular target for the clinical diagnosis and treatment of HCC.

Fbxw11 Variants Promotes Proliferation of Leukemia Cells By Activating the NF-κB Signaling Pathway

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 894-894
Author(s):  
Lina Wang ◽  
Jinfeng Liao ◽  
Wenli Feng ◽  
Xiao Yang ◽  
Shayan Chen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Leukemia Cells ◽  
Control Group ◽  
Over Expression

Abstract Fbxw11, as a member of F-box proteins family, is a constituent of the SCF (Skp1-Cul1-F box) ubiquitin ligase complex. This ligase ubiquitinates specifically phosphorylated substrates and controls the degradation and half-life of key cellular regulators. So, Fbxw11 play a pivotal role in many aspects of hematopoiesis and tumorigenesis through regulating various signal transduction pathways. We found two transcript variants (Fbxw11c and Fbxw11d) in mouse bone marrow. However the role of Fbxw11 variants in the development of leukemia and the underlying mechanisms remain largely unknown. In this study, we cloned three transcript variants (Fbxw11a, Fbxw11c and Fbxw11d) to study the biological function of Fbxw11 in leukemia. In order to investigate the role of Fbxw11 variants in leukemia, we established L1210 cell lines with over-expression of Fbxw11a, Fbxw11c and Fbxw11d respectively using the lentivirus system. The effect of Fbxw11 variants on proliferation of leukemia cells in vitro was first detected. Growth curve of leukemia cells with Fbxw11a, Fbxw11c or Fbxw11d over-expression was established by cell counting. The results suggested that over-expression of Fbxw11 variants stimulated the growth of leukemia cells. Then MTT experiment was carried out to study the effect of Fbxw11 variants on leukemia cell proliferation and the results showed that Fbxw11 variants increased the proliferation of L1210 cells in vitro. To further confirm the effects of Fbxw11 variants on proliferation of leukemia cells in vivo, tumor xenografts model with over-expression of Fbxw11a, Fbxw11c and Fbxw11d in DBA/2 mice was established. Leukemia cells L1210 with over-expression of Fbxw11a, Fbxw11c and Fbxw11d respectively were transplanted into DBA/2 mice by hypodermic injection. The tumor growth curves showed that tumor growth was increased in Fbxw11 variants over-expression group compared to the control group. Mice were sacrificed on day 28 after transplantation, greater volume of the xenograft tumors were obtained from Fbxw11 variants over-expression group than control group. Therefore, Over-expression of Fbxw11 variants could increase growth of tumor in vivo. To further investigate the molecular mechanism under the effect of Fbxw11 variants on proliferation of leukemia cells, we tested the apoptosis and cell cycle of leukemia cells with Fbxw11 variants over-expression. Over-expression of Fbxw11 variants did not affect the cell apoptosis but accelerated the process of cell cycle. These results revealed that the increased cell proliferation was not due to decrease in cell apoptosis but due to increase in cell cycle. In addition, we tested the effect of Fbxw11 variants on the signal transduction by dual-luciferase reporter gene system. The results showed that over-expression of Fbxw11 variants caused the activation of NF-κB signaling pathway. In conclusion, our findings suggest that Fbxw11 variants have promoting effect on cell proliferation of leukemia cells. The effect of Fbxw11 variants on cell proliferation are due to accelerated the process of cell cycle but not decreasing in cell apoptosis. Further study demonstrated that Fbxw11 variants promote cell proliferation through activating the NF-κB signaling pathway. The important role of Fbxw11 in regulating the development of leukemia suggests that a potent rationale for developing Fbxw11 as a potential therapeutic target against leukemia. Disclosures No relevant conflicts of interest to declare.

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