Mitogen‐activated protein kinase (MEK/ERK) inhibition sensitizes cancer cells to centromere‐associated protein E inhibition

Mayes, Patrick A.; Degenhardt, Yan; Wood, Andrew C.; Toporovskya, Yana; Diskin, Sharon J.; Haglund, Elizabeth; Moy, Christopher; Wooster, Richard; Maris, John M.

doi:10.1002/ijc.27781

Cited by 17 publications

(13 citation statements)

References 36 publications

(66 reference statements)

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“…The increased cell death by MEK/paclitaxel combination is associated with the cooperative up-regulation of the pro-apoptotic protein Bim and down-regulation of the anti-apoptotic protein Mcl-1 43 . MEK/ERK inhibition could also sensitize neuroblastoma cells to the inhibitors of centromere-associated protein E (CENP E), a kinesin motor protein that is critical for chromosome attachment to mitotic spindles 44 . Moreover, combined inhibition of MEK and Plk1 elicits synergistic antitumor activity specifically in NRAS mutant melanoma 24 .…”

Section: Discussionmentioning

confidence: 99%

Anti-Melanoma Activities of Haspin Inhibitor CHR-6494 Deployed as a Single Agent or in a Synergistic Combination with MEK Inhibitor

et al. 2017

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Background: Melanoma is a heterogeneous malignancy that presents an immense challenge in therapeutic development. Recent approaches targeting the oncogenic MAP kinase pathways have shown tremendous improvement in the overall survival of patients with advanced melanoma. However, there is still an urgent need for identification of new strategies to overcome drug resistances and to improve therapeutic efficacy. Haspin (Haploid Germ Cell-Specific Nuclear Protein Kinase) belongs to a selected group of mitotic kinases and is required for normal mitosis progression. In contrast to inhibitors of other mitotic kinases, anti-tumor potential of haspin inhibitors has not been well explored. Herein, we aim to examine effects of CHR-6494, a small molecule inhibitor of haspin, in melanoma cells.Methods: Anti-tumor activities of the haspin inhibitor CHR-6494 were tested in a number of melanoma cell lines either as a single agent or in combination with the MEK inhibitor Trametinib (GSK1120212). Experiments are based on: 1) Cell viability determined by the crystal violet staining assay; 2) apoptotic responses measured by the caspase 3/7 activity assay and western blot analysis for the level of cleaved PARP (Poly ADP-Ribose Polymerase); 3) cell cycle analysis conducted using flow cytometry; and 4) cell migratory ability assessed by the scratch assay and the transwell migration assay.Results: We have found that CHR-6494 alone elicits a dose dependent inhibitory effect on the viability of several melanoma cell lines. This growth inhibition is accompanied by an increase in apoptotic responses. More importantly, CHR-6494 appears to synergize with the MEK inhibitor Trametinib in suppressing cell growth and enhancing apoptosis in both wild type and BRAFV600E mutant melanoma cell lines. Administering of these two small molecules as a combination is also capable of suppressing cell migration to a greater extent than the individual agent.Conclusion: These results suggest that haspin can be considered as a viable anti-melanoma target, and that concomitant inhibition of haspin and MEK activities with small molecules could represent a novel therapeutic strategy with improved efficacy for treatment of melanoma.

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Section: Discussionmentioning

confidence: 99%

Anti-Melanoma Activities of Haspin Inhibitor CHR-6494 Deployed as a Single Agent or in a Synergistic Combination with MEK Inhibitor

et al. 2017

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“…GSK923295 is an allosteric inhibitor of CENP-E that blocks its microtubule stimulated ATPase activity and stabilizes the interaction between the motor domain and microtubules [449,450]. GSK923295 has demonstrated both in vitro and in vivo antitumor activity against various malignancies [449,451,452,453,454,455]. Cells treated with GSK923925 assemble bipolar spindles and the majority of chromosomes align at the spindle equator.…”

Section: Targeting Chromosome Congression For Cancer Therapymentioning

confidence: 99%

“…However, some chromosomes remain clustered near the spindle poles, leading to mitotic arrest and apoptosis [449,456]. The antitumor activity of GSK923925 has been evaluated in combination with standard chemotherapies, as well as with other emerging targeted drugs [454]. Inhibition of ERK1 revealed a significant synergistic proliferation inhibition activity when combined with GSK923225 in neuroblastoma, lung, pancreatic and colon carcinoma cell lines [454].…”

Section: Targeting Chromosome Congression For Cancer Therapymentioning

confidence: 99%

“…The antitumor activity of GSK923925 has been evaluated in combination with standard chemotherapies, as well as with other emerging targeted drugs [454]. Inhibition of ERK1 revealed a significant synergistic proliferation inhibition activity when combined with GSK923225 in neuroblastoma, lung, pancreatic and colon carcinoma cell lines [454]. Combination of GSK923225 with Pgp-pump modulators also appeared to improve the antitumor effects against cells with Pgp overexpression, thereby overcoming the resistance to Pgp inhibitors [457].…”

Section: Targeting Chromosome Congression For Cancer Therapymentioning

confidence: 99%

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Mechanisms of Chromosome Congression during Mitosis

Maiato

Gomes

Sousa

et al. 2017

Biology

161

176

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Chromosome congression during prometaphase culminates with the establishment of a metaphase plate, a hallmark of mitosis in metazoans. Classical views resulting from more than 100 years of research on this topic have attempted to explain chromosome congression based on the balance between opposing pulling and/or pushing forces that reach an equilibrium near the spindle equator. However, in mammalian cells, chromosome bi-orientation and force balance at kinetochores are not required for chromosome congression, whereas the mechanisms of chromosome congression are not necessarily involved in the maintenance of chromosome alignment after congression. Thus, chromosome congression and maintenance of alignment are determined by different principles. Moreover, it is now clear that not all chromosomes use the same mechanism for congressing to the spindle equator. Those chromosomes that are favorably positioned between both poles when the nuclear envelope breaks down use the so-called “direct congression” pathway in which chromosomes align after bi-orientation and the establishment of end-on kinetochore-microtubule attachments. This favors the balanced action of kinetochore pulling forces and polar ejection forces along chromosome arms that drive chromosome oscillatory movements during and after congression. The other pathway, which we call “peripheral congression”, is independent of end-on kinetochore microtubule-attachments and relies on the dominant and coordinated action of the kinetochore motors Dynein and Centromere Protein E (CENP-E) that mediate the lateral transport of peripheral chromosomes along microtubules, first towards the poles and subsequently towards the equator. How the opposite polarities of kinetochore motors are regulated in space and time to drive congression of peripheral chromosomes only now starts to be understood. This appears to be regulated by position-dependent phosphorylation of both Dynein and CENP-E and by spindle microtubule diversity by means of tubulin post-translational modifications. This so-called “tubulin code” might work as a navigation system that selectively guides kinetochore motors with opposite polarities along specific spindle microtubule populations, ultimately leading to the congression of peripheral chromosomes. We propose an integrated model of chromosome congression in mammalian cells that depends essentially on the following parameters: (1) chromosome position relative to the spindle poles after nuclear envelope breakdown; (2) establishment of stable end-on kinetochore-microtubule attachments and bi-orientation; (3) coordination between kinetochore- and arm-associated motors; and (4) spatial signatures associated with post-translational modifications of specific spindle microtubule populations. The physiological consequences of abnormal chromosome congression, as well as the therapeutic potential of inhibiting chromosome congression are also discussed.

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“…In particular, the ERK signaling pathway which universally governs proliferation, differentiation and cell survival, is associated with resistance to apoptosis in malignant tumors. Many studies showed that inactivation of this pathway sensitizes cancer cells to anti-cancer drugs induced apoptosis, 26,27 and the subject of intense research scrutiny leading to the development of pharmacologic inhibitors for the treatment of cancer. Yao et al 28 demonstrated that Trop-2 has the ability to activate ERK using gene-reporter assays, and Trop-2 expression contributes to tumor by activating the ERK/MAPK pathway.…”

Section: Discussionmentioning

confidence: 99%

Chemotherapy agents-induced immunoresistance in lung cancer cells could be reversed by trop-2 inhibition in vitro and in vivo by interaction with MAPK signaling pathway

Wang

Long

Dong

et al. 2013

Cancer Biology & Therapy

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Chemotherapy has been widely used in cancer treatment, but the prognosis of the cancer patients following chemotherapy has not been substantially improved. Alternative strategies such as immunotherapy and their combinations with chemotherapy are now being considered; however, the effects of chemotherapy on the immune responses of cancer cells are not fully understood. In the present studies, we reveal a potential link between chemotherapy and cancer immunoresistance, we first examined the effects of chemopreventive agent DDP on the expression of a cell surface glycopreotein Trop-2 in lung cancer cells, and found that DDP not only induce Trop-2 surface expression in human lung cancer cells, but also induce T-cell apoptosis effectively. In order to investigate the relationship between DDP-induced Trop-2 expression and T-cell apoptosis, we stably transfected A549 and PC14 lung cancer cells with Trop-2 shRNA, the DDP-induced Trop-2 surface expression was effectively decreased in stably transfected cell lines, but chemotherapeutic reagent-induced cell proliferation inhibition and apoptosis were increased through inhibition of the MAPK signaling pathway. In vivo animal experiments showed that Trop-2 knockdown tumors displayed a slower growth rate than the control xenografts. Importantly, DDP treatment exhibited a strong antitumor activity in the mice with Trop-2 knockdown tumors, but only a marginal effect in the control group. Taken together, our data show that DDP resistance in lung cancer cells could be induced through increased surface expression of Trop-2, which at least partially by interfering with MAPK pathway. These results provide novel insight into the function of Trop-2 and encourage the design and testing of approaches targeting this protein and its partners.

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Mitogen‐activated protein kinase (MEK/ERK) inhibition sensitizes cancer cells to centromere‐associated protein E inhibition

Cited by 17 publications

References 36 publications

Anti-Melanoma Activities of Haspin Inhibitor CHR-6494 Deployed as a Single Agent or in a Synergistic Combination with MEK Inhibitor

Anti-Melanoma Activities of Haspin Inhibitor CHR-6494 Deployed as a Single Agent or in a Synergistic Combination with MEK Inhibitor

Mechanisms of Chromosome Congression during Mitosis

Chemotherapy agents-induced immunoresistance in lung cancer cells could be reversed by trop-2 inhibition in vitro and in vivo by interaction with MAPK signaling pathway

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