Targeting Insulin-Like Growth Factor 1 Receptor Delays M-Phase Progression and Synergizes with Aurora B Inhibition to Suppress Cell Proliferation

Yamagishi, Akane; Ikeda, Yuki; Ikeuchi, Masayoshi; Yuki, Ryuzaburo; Saito, Youhei; Nakayama, Yuji

doi:10.3390/ijms21031058

Cited by 7 publications

(11 citation statements)

References 45 publications

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“…Furthermore, the cleaved caspase-3–positive cells were observed in the cells treated by inhibitors and the number of cleaved caspase-3–positive cells were significantly increased upon the combination treatment ( Figure 1 a,b). Considering that the number of cells after 72 h of combination treatment was less than that of seeded cells (Figure 7B in [ 16 ]), these results suggest an involvement of cell death in suppression of cell proliferation. It is worthy to note that the cleaved caspase-3–positive cells generated by the combination treatment appear to be larger than those obtained by either OSI-906 or ZM447439 treatment ( Figure 1 a).…”

Section: Resultsmentioning

confidence: 99%

“…A retrospective analysis of patients with cervical cancer showed that IGF1/IGF1R signaling is involved in tumor formation and clinical outcome [ 8 ]. We previously reported that although 3 µM OSI-906 suppressed 48% of cell proliferation, combination with 1 µM ZM447439, which caused almost no suppressive effect, suppressed 74% of cell proliferation of cervical cancer HeLa S3 cells [ 16 ]. However, the precise mechanism behind this effect is yet to be elucidated.…”

Section: Resultsmentioning

confidence: 99%

“…We previously reported that OSI-906 delays M phase progression [ 16 ]. ZM447439 is an inhibitor of Aurora B, a protein that is critical for M phase progression.…”

Section: Resultsmentioning

confidence: 99%

“…This is supported by the fact that increases in plasma IGF1 levels are associated with cancer risk [ 9 , 10 , 11 , 12 ]. Recently, we reported an abnormal cell division upon inhibition of receptor-type tyrosine kinases, including EphA2 [ 13 ], ALK [ 14 ], VEGF receptor [ 15 ], and IGF1R [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, combination therapy of anti-mitotic drugs with compounds targeting cancer-specific alterations must be useful to reduce the side effects. Recently, we reported that targeting IGF1R combined with Aurora B inhibition suppresses cell proliferation more than single treatment [ 16 ]. However, the molecular mechanisms underlying the suppressive effect of this combination on cell proliferation is yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Combination Treatment of OSI-906 with Aurora B Inhibitor Reduces Cell Viability via Cyclin B1 Degradation-Induced Mitotic Slippage

Ikeda

Yasutake

Yuki

et al. 2021

IJMS

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Insulin-like growth factor 1 receptor (IGF1R), a receptor-type tyrosine kinase, transduces signals related to cell proliferation, survival, and differentiation. We recently reported that OSI-906, an IGF1R inhibitor, in combination with the Aurora B inhibitor ZM447439 suppresses cell proliferation. However, the mechanism underlying this suppressive effect is yet to be elucidated. In this study, we examined the effects of combination treatment with OSI-906 and ZM447439 on cell division, so as to understand how cell proliferation was suppressed. Morphological analysis showed that the combination treatment generated enlarged cells with aberrant nuclei, whereas neither OSI-906 nor ZM447439 treatment alone caused this morphological change. Flow cytometry analysis indicated that over-replicated cells were generated by the combination treatment, but not by the lone treatment with either inhibitors. Time-lapse imaging showed mitotic slippage following a severe delay in chromosome alignment and cytokinesis failure with furrow regression. Furthermore, in S-trityl-l-cysteine–treated cells, cyclin B1 was precociously degraded. These results suggest that the combination treatment caused severe defect in the chromosome alignment and spindle assembly checkpoint, which resulted in the generation of over-replicated cells. The generation of over-replicated cells with massive aneuploidy may be the cause of reduction of cell viability and cell death. This study provides new possibilities of cancer chemotherapy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…We previously reported that OSI-906 delays M phase progression [ 16 ]. ZM447439 is an inhibitor of Aurora B, a protein that is critical for M phase progression.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Combination Treatment of OSI-906 with Aurora B Inhibitor Reduces Cell Viability via Cyclin B1 Degradation-Induced Mitotic Slippage

Ikeda

Yasutake

Yuki

et al. 2021

IJMS

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TNK2 Inhibitor (R)−9bMS Causes Polyploidization Through Mitotic Failure by Targeting Aurora B

Murata,

Kuwajima,

Tanaka

et al. 2024

Cell Biochemistry & Function

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TNK2 is a ubiquitously expressed nonreceptor‐type tyrosine kinase. TNK2 participates in tumorigenesis, and TNK2 activation has been found in various cancers; therefore, TNK2 is a promising target for cancer chemotherapy. While the TNK2 inhibitor XMD16‐5 is highly selective, it inhibits cytokinesis at higher concentrations by targeting Aurora B kinase, a key enzyme for cell division. Cytokinesis failure frequently generates polyploid cells, and the surviving polyploid cells risk leading to cancer development and malignant progression via chromosome instability. In this study, to investigate the possibility that (R)−9bMS, a TNK2 inhibitor structurally related to XMD16‐5, drives malignant progression by inducing abnormal cell division, we examined its effects on cell division, Aurora B autophosphorylation, and colony formation. Cell count results showed a reduction in the number of A431, HeLa S3, HCT116, and MCF7 cells upon TNK2 inhibitor treatment. Microscopic observation indicated the formation of multinucleated and nucleus‐enlarged cells. An increase in DNA content was confirmed with flow cytometry, which was underpinned by an increased number of centrosomes. Time‐lapse imaging revealed mitotic failure, such as mitotic slippage and cytokinesis failure, as a cause of polyploidization. Of note, TNK2 knockdown significantly increased multinucleated cells, but the effect was quite weak, suggesting that TNK2 inhibition may only partially contribute to mitotic failure and polyploidization. Expectedly, Aurora B phosphorylation was reduced by (R)−9bMS like XMD16‐5, but not by TNK2 knockdown. Collectively, TNK2 inhibitors (R)−9bMS and XMD16‐5 induce polyploidization via mitotic failure caused by the inhibition of Aurora B kinase rather than TNK2. Notably, (R)−9bMS treatment promoted anchorage‐independent colony formation, a hallmark of cancer. Our findings suggest that (R)−9bMS at a high concentration risks promoting cancer development or malignant progression. Therefore, caution should be used when using TNK2 inhibitors for cancers where TNK2 activation is not the transforming mutation and higher concentrations of TNK2 inhibitors are required to slow proliferation.

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Phosphorylation of Ephexin4 at Ser-41 contributes to chromosome alignment via RhoG activation in cell division

Yasutake,

Kuwajima,

Yuki

et al. 2024

Journal of Biological Chemistry

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Targeting Insulin-Like Growth Factor 1 Receptor Delays M-Phase Progression and Synergizes with Aurora B Inhibition to Suppress Cell Proliferation

Cited by 7 publications

References 45 publications

Combination Treatment of OSI-906 with Aurora B Inhibitor Reduces Cell Viability via Cyclin B1 Degradation-Induced Mitotic Slippage

Combination Treatment of OSI-906 with Aurora B Inhibitor Reduces Cell Viability via Cyclin B1 Degradation-Induced Mitotic Slippage

TNK2 Inhibitor (R)−9bMS Causes Polyploidization Through Mitotic Failure by Targeting Aurora B

Phosphorylation of Ephexin4 at Ser-41 contributes to chromosome alignment via RhoG activation in cell division

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