Inhibiting cancer cell hallmark features through nuclear export inhibition

Sun, Qingxiang; Chen, Xueqin; Zhou, Qiao; Burstein, Ezra; Yang, Shengyong; Jia, Da

doi:10.1038/sigtrans.2016.10

Cited by 102 publications

(134 citation statements)

References 174 publications

(244 reference statements)

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“…CRM1 has been observed to play a role in inflammatory diseases, viral infections, wound healing, and most notably in cancer [10]. The overexpression of CRM1 seen in many different types of cancers is correlated with increased metastasis, histological grade, tumor size, and decreased survival [11,12].…”

Section: Introductionmentioning

confidence: 99%

Leptomycin B alters the subcellular distribution of CRM1 (Exportin 1)

Rahmani

Dean

2017

Biochemical and Biophysical Research Communications

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CRM1 (chromosome maintenance region 1, Exportin 1) binds to nuclear export signals and is required for nucleocytoplasmic transport of a large variety of proteins and RNP complexes. Leptomycin B (LMB), the first specific inhibitor of CRM1 identified, binds covalently to cysteine 528 in the nuclear export signal binding region of CRM1 leading to the inhibition of protein nuclear export. Although the biochemical mechanisms of action of CRM1 inhibitors such as LMB are well studied, the subcellular effects of inhibition on CRM1 are unknown. We have found that LMB causes CRM1 to redistribute from the nucleus to the cytoplasm in A549 cells. A significant decrease in nuclear CRM1 coupled with an increase in cytoplasmic CRM1 was sustained for up to 4 hours, while there was no change in total CRM1 protein in fractionated cells. Cells expressing an LMB insensitive HA-tagged CRM1-C528S protein were unaffected by LMB treatment, whereas HA-tagged wildtype CRM1 redistributed from the nucleus to the cytoplasm with LMB treatment, similar to endogenous CRM1. GFP-tagged CRM1 protein microinjected into the cytoplasm of A549 cells distributed throughout the cell in untreated cells remained primarily cytoplasmic in LMB-treated cells. Upon nuclear microinjection, GFP-CRM1 translocated to and accumulated in the cytoplasm of LMB-treated cells. Thus, LMB binds to CRM1 and causes its redistribution to the cytoplasm by inhibiting its nuclear import. Decreasing the nuclear availability of CRM1 likely contributes to the accumulation of CRM1 cargo proteins in the nucleus, suggesting a new mechanism of action for LMB.

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Section: Introductionmentioning

confidence: 99%

Leptomycin B alters the subcellular distribution of CRM1 (Exportin 1)

Rahmani

Dean

2017

Biochemical and Biophysical Research Communications

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“…Taken together, CRM1 inhibition might be an interesting therapeutic option in NUP214related leukemia, similarly as described for several cancer models, including other forms of leukemia 23,24,29,54,55 . This notion is further supported by a recent study that showed successful disease remission for an AML patient with NUP214 driven leukemia who was treated with KPT-330 as single agent 56,57 .…”

Section: Discussionmentioning

confidence: 60%

“…In fact, both fusion proteins can bind CRM1 and its co-factor, the small GTPase Ran, and inhibit the nuclear export of NES-containing proteins and RNPs 17,18 . Targeted CRM1 inhibition by small molecule antagonists has become an appealing anti-cancer strategy, for both solid and hematologic malignancies [20][21][22][23][24] . Leptomycin B (LMB), a fungal metabolite from Streptomyces spp, was the first identified small molecule inhibitor specifically targeting CRM1 25 .…”

Section: Introductionmentioning

confidence: 99%

Targeted CRM1-inhibition perturbs leukemogenic NUP214 fusion proteins and exerts anti-cancer effects in leukemia cell lines withNUP214rearrangements

Mendes

Juehlen

Martinelli

et al. 2020

Preprint

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Chromosomal translocations fusing the locus of nucleoporin NUP214 each with the protooncogenes SET and DEK are recurrent in, largely intractable, acute leukemias. The molecular basis underlying the pathogenesis of SET-NUP214 and DEK-NUP214 are still poorly understood, but both chimeras inhibit protein nuclear export mediated by the ß-karyopherin CRM1. In this report, we show that SET-NUP214 and DEK-NUP214 both disturb the localization of proteins essential for nucleocytoplasmic transport, in particular for CRM1mediated protein export. Endogenous and exogenous SET-NUP214 and DEK-NUP214 form nuclear bodies. These nuclear bodies disperse upon targeted inhibition of CRM1 and the two fusion proteins re-localize throughout the nucleoplasm. Moreover, SET-NUP214 and DEK-NUP214 nuclear bodies reestablish shortly after removal of CRM1 inhibitors. Likewise, cell viability, metabolism, and proliferation of leukemia cell lines harboring SET-NUP214 and DEK-NUP214 are compromised by CRM1 inhibition, which is even sustained after clearance from CRM1 antagonists. Our results indicate CRM1 as a possible therapeutic target in NUP214related leukemia. This is especially important, since no specific or targeted treatment options for NUP214 driven leukemia are available yet.

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“…Currently, the modulation of protein function by specific signal transduction inhibitors is one of the therapeutic tools for CML [25][26][27]. In this study, we examined the effects of a small molecule, TH-39, which potentially targets the Hec1/Nek2 interaction, and our results indicated that TH-39 exhibited antitumor efficacy in K562 cells via G0/G1 cell cycle arrest and apoptosis induction.…”

Section: Discussionmentioning

confidence: 95%

Small Molecule TH-39 Potentially Targets Hec1/Nek2 Interaction and Exhibits Antitumor Efficacy in K562 Cells via G0/G1 Cell Cycle Arrest and Apoptosis Induction

Zhu

Wei²,

Ye³

et al. 2016

Cell Physiol Biochem

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Background: Cancer is still a major public health issue worldwide, and new therapeutics with anti-tumor activity are still urgently needed. Methods: The anti-tumor activity of TH-39, which shows potent anti-proliferative activity against K562 cells with an IC₅₀ of 0.78 µM, was investigated using immunoblot, co-immunoprecipitation, the MTT assay, and flow cytometry. Results: Mechanistically, TH-39 may disrupt the interaction between Hec1 and Nek2 in K562 cells. Moreover, TH-39 inhibited cell proliferation in a concentration- and time-dependent manner by influencing the morphology of K562 cells and inducing G0/G1 phase arrest. G0/G1 phase arrest was associated with down-regulation of CDK2-cyclin E complex and CDK4/6-cyclin D complex activities. Furthermore, TH-39 also induced cell apoptosis, which was associated with activation of caspase-3, down-regulation of Bcl-2 expression and up-regulation of Bax. TH-39 could also decrease mitochondrial membrane potential (Δψm) and increase reactive oxygen species (ROS) accumulation in K562 cells. The results indicated that TH-39 might induce apoptosis via the ROS-mitochondrial apoptotic pathway. Conclusion: This study highlights the potential therapeutic efficacy of the anti-cancer compound TH-39 in treatment-resistant chronic myeloid leukemia.

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Inhibiting cancer cell hallmark features through nuclear export inhibition

Cited by 102 publications

References 174 publications

Leptomycin B alters the subcellular distribution of CRM1 (Exportin 1)

Leptomycin B alters the subcellular distribution of CRM1 (Exportin 1)

Targeted CRM1-inhibition perturbs leukemogenic NUP214 fusion proteins and exerts anti-cancer effects in leukemia cell lines withNUP214rearrangements

Small Molecule TH-39 Potentially Targets Hec1/Nek2 Interaction and Exhibits Antitumor Efficacy in K562 Cells via G0/G1 Cell Cycle Arrest and Apoptosis Induction

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