Induction of apoptosis by directing oncogenic Bcr-Abl into the nucleus

Huang, Zhenglan; Gao, Miao; Li, Qianyin; Tao, Kun; Xiao, Qing; Cao, Weixi; Feng, Wenli

doi:10.18632/oncotarget.1339

Cited by 14 publications

(20 citation statements)

References 49 publications

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“…8,9 Figure 1A demonstrates the process of XPO1-mediated nuclear export. Importantly, it is the sole nuclear exporter of several classes of critical cancer-related proteins, 10 [11][12][13][14][15][16][17][18] ; (2) cell cycle regulators (eg, p21, p27, galectin-3, Tob) 19-22 ; (3) immune response regulators (eg, inhibitor of NF-kB, IkB) 23 ; (4) oncogenes (eg, BCR-ABL) 24 ; and (5) chemotherapeutic targets (eg, DNA topoisomerases I and II). 25 In addition, XPO1 forms a complex with the messenger RNA (mRNA) capbinding protein eukaryotic initiation factor 4E (eIF4E) to transport multiple oncoprotein mRNAs (eg, c-Myc, cyclin D1, MDM2) to the cytoplasm, promoting synthesis of oncoproteins.…”

Section: Role Of Xpo1 In Cancermentioning

confidence: 99%

Clinical Implications of Targeting XPO1-mediated Nuclear Export in Multiple Myeloma

Gandhi

Senapedis

Baloglu

et al. 2018

Clinical Lymphoma Myeloma and Leukemia

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Multiple myeloma (MM) is a malignancy of plasma cells that is typically chronic, and relapse is common. Current therapeutic strategies include combination and sequential treatments with corticosteroids, alkylating agents, proteasomal inhibitors, immunomodulators, and monoclonal antibodies. These drugs prolong survival but ultimately become ineffective. Exportin 1 (XPO1), a nuclear export protein, is overexpressed in MM cells, and knockdown studies have suggested that XPO1 is essential for MM cell survival. Selective inhibitor of nuclear export (SINE) compounds are novel, orally bioavailable class of agents that specifically inhibit XPO1. Selinexor (KPT-330) is the first-in-human SINE compound. Early phase clinical trials have established the safety profile of this agent and have shown promising efficacy in combination with low-dose dexamethasone and other anti-MM agents. The combination of selinexor and dexamethasone has demonstrated activity in "penta-refractory" MM, (ie, MM refractory to the 5 most active anti-MM agents currently used in treatment). We have reviewed the available data on the molecular implications of XPO1 inhibition in MM. We also reviewed the pertinent early phase clinical data with SINE compounds and discuss management strategies for common toxicities encountered with use of selinexor.

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Section: Role Of Xpo1 In Cancermentioning

confidence: 99%

Clinical Implications of Targeting XPO1-mediated Nuclear Export in Multiple Myeloma

Gandhi

Senapedis

Baloglu

et al. 2018

Clinical Lymphoma Myeloma and Leukemia

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“…In our study, RanGAP1 knockdown by shRNA or miR-1301 increased the protein levels of the cleaved form of PARP and Bax in IM-treated K562 cells (Figs 2A and 6A ). Activation of P73 and its downstream pathway has been reported to induce CML cell apoptosis, which is triggered by nuclear BCR-ABL [ 11 , 31 ]. P73 binds and transactivates the Bax gene promoter to induce apoptosis in irradiated T cells and ovarian cancer cells [ 32 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…The BCR-ABL protein localizes exclusively in the cell cytoplasm because its kinase domain masks the nuclear localization sequence (NLS); therefore, IM can release the NLS domain to induce BCR-ABL nuclear import [ 6 – 8 ]. Nuclear BCR-ABL can be re-activated either by the removal of IM or through the metabolic decay of IM, and subsequently phosphorylated the Tyr-99 of P73 to trigger apoptosis [ 9 – 11 ]. Altogether, these results suggest that impairment of BCR-ABL nuclear export can induce P73-dependent apoptosis which would be used as a strategy for improving IM efficacy.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-1301-Mediated RanGAP1 Downregulation Induces BCR-ABL Nuclear Entrapment to Enhance Imatinib Efficacy in Chronic Myeloid Leukemia Cells

et al. 2016

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Chronic myeloid leukemia (CML) is a myeloproliferative disease. Imatinib (IM), the first line treatment for CML, is excessively expensive and induces various side effects in CML patients. Therefore, it is essential to investigate a new strategy for improving CML therapy. Our immunoblot data revealed that RanGTPase activating protein 1 (RanGAP1) protein levels increased by approximately 30-fold in K562 cells compared with those in normal cells. RanGAP1 is one of the important components of RanGTPase system, which regulates the export of nuclear protein. However, whether RanGAP1 level variation influences BCR-ABL nuclear export is still unknown. In this report, using shRNA to downregulate RanGAP1 expression level augmented K562 cell apoptosis by approximately 40% after treatment with 250 nM IM. Immunofluorescence assay also indicated that three-fold of nuclear BCR-ABL was detected. These data suggest that BCR-ABL nuclear entrapment induced by RanGAP1 downregulation can be used to improve IM efficacy. Moreover, our qRT-PCR data indicated a trend of inverse correlation between the RanGAP1 and microRNA (miR)-1301 levels in CML patients. MiR-1301, targeting the RanGAP1 3′ untranslated region, decreased by approximately 100-fold in K562 cells compared with that in normal cells. RanGAP1 downregulation by miR-1301 transfection impairs BCR-ABL nuclear export to increase approximately 60% of cell death after treatment of 250 nM IM. This result was almost the same as treatment with 1000 nM IM alone. Furthermore, immunofluorescence assay demonstrated that Tyr-99 of nuclear P73 was phosphorylated accompanied with nuclear entrapment of BCR-ABL after transfection with RanGAP1 shRNA or miR-1301 in IM-treated K562 cells. Altogether, we demonstrated that RanGAP1 downregulation can mediate BCR-ABL nuclear entrapment to activate P73-dependent apoptosis pathway which is a novel strategy for improving current IM treatment for CML.

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“…To obtain cytoplasmic and nuclear proteins respectively, a Nuclear and Cytoplasmic Protein Extraction Kit (KeyGEN, Nanjing, China) was used. Western blot procedures were performed as previously [44]. Antibodies against c-Abl, Bax, STAT5, phospho-STAT5, PARP, caspase-3, p73, phospho-p73, Akt, phospho-Akt, Glycogen synthase kinase (GSK), and phospho-GSK were bought from Cell Signaling Technology; antibody against FLAG from Sigma (St. Louis, MO, USA); antibodies against p21, PUMA, MAPK, phospho-MAPK, ERK, phospho-ERK, HA, and Actin from Santa Cruz Biotechnology (Dallas, TX, USA).…”

Section: Methodsmentioning

confidence: 99%

Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells

Huang

Gao

et al. 2017

IJMS

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The gradual emerging of resistance to imatinib urgently calls for the development of new therapy for chronic myeloid leukemia (CML). The fusion protein Bcr-Abl, which promotes the malignant transformation of CML cells, is mainly located in the cytoplasm, while the c-Abl protein which is expressed in the nucleus can induce apoptosis. Based on the hetero-dimerization of FKBP (the 12-kDa FK506- and rapamycin-binding protein) and FRB (the FKBP-rapamycin binding domain of the protein kinase, mTOR) mediated by AP21967, we constructed a nuclear transport system to induce cytoplasmic Bcr-Abl into nuclear. In this study, we reported the construction of the nuclear transport system, and we demonstrated that FN3R (three nuclear localization signals were fused to FRBT2098L with a FLAG tag), HF2S (two FKBP domains were in tandem and fused to the SH2 domain of Grb2 with an HA tag) and Bcr-Abl form a complexus upon AP21967. Bcr-Abl was imported into the nucleus successfully by the nuclear transport system. The nuclear transport system inhibited CML cell proliferation through mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 5 (STAT5) pathways mainly by HF2S. It was proven that nuclear located Bcr-Abl induced CML cell (including imatinib-resistant K562G01 cells) apoptosis by activation of p73 and its downstream molecules. In summary, our study provides a new targeted therapy for the CML patients even with Tyrosine Kinase Inhibitor (TKI)-resistance.

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Induction of apoptosis by directing oncogenic Bcr-Abl into the nucleus

Cited by 14 publications

References 49 publications

Clinical Implications of Targeting XPO1-mediated Nuclear Export in Multiple Myeloma

Clinical Implications of Targeting XPO1-mediated Nuclear Export in Multiple Myeloma

MicroRNA-1301-Mediated RanGAP1 Downregulation Induces BCR-ABL Nuclear Entrapment to Enhance Imatinib Efficacy in Chronic Myeloid Leukemia Cells

Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells

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