MKLP2 functions in early mitosis to ensure proper chromosome congression

Schrock, Morgan S.; Scarberry, Luke; Stromberg, Benjamin R.; Sears, Claire; Torres, Adrian; Tallman, David; Krupinski, Lucas; Chakravarti, Arnab; Summers, Matthew K.

doi:10.1242/jcs.259560

Cited by 6 publications

(3 citation statements)

References 56 publications

(41 reference statements)

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“…A previous study has showed that the NGFR-AMPK-mTOR pathway was elevated by resveratrol to induce autophagy and apoptosis in A549 cells [ 19 ]. KIF20A, also known as mitotic kinesin-like protein 2 (MKLP2), plays an essential role in mitosis by serving as a kinesin to protect cells from chromosomal instability, and drives cytokinesis [ 20 ].…”

Section: Resultsmentioning

confidence: 99%

Metochalcone induces senescence-associated secretory phenotype via JAK2/STAT3 pathway in breast cancer

ZHOU,

WAN,

XIAO

et al. 2024

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Breast and lung cancers are the leading causes of mortality and most frequently diagnosed cancers in women and men, respectively, worldwide. Although the antitumor activity of chalcones has been extensively studied, the molecular mechanisms of isoliquiritigenin analog 2', 4', 4-trihydroxychalcone (metochalcone; TEC) against carcinomas remain less well understood. In this study, we found that TEC inhibited cell proliferation of breast cancer BT549 cells and lung cancer A549 cells in a concentration-dependent manner. TEC induced cell cycle arrest in the S-phase, cell migration inhibition in vitro , and reduced tumor growth in vivo . Moreover, transcriptomic analysis revealed that TEC modulated the activity of the JAK2/STAT3 and P53 pathways. TEC triggered the senescence-associated secretory phenotype (SASP) by repressing the JAK2/STAT3 axis. The mechanism of metochalcone against breast cancer depended on the induction of SASP via deactivation of the JAK2/STAT3 pathway, highlighting the potential of chalcone in senescence-inducing therapy against carcinomas.

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Section: Resultsmentioning

confidence: 99%

Metochalcone induces senescence-associated secretory phenotype via JAK2/STAT3 pathway in breast cancer

ZHOU,

WAN,

XIAO

et al. 2024

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“…LXY18 treatment recapitulates multiple defects seen after inhibition of MKLP2, including AURKB relocation failure, the mitotic arrest, and multipolarity 16,30,31 . These similarities point to the possibility of MKLP2 as a target for LXY18.…”

Section: Lxy18 As a Myc-primed Mitotic Blockermentioning

confidence: 86%

MYC amplifies mitotic perturbations elicited by LXY18 to enable synthetic lethality

Kalashova,

Yang,

Long

et al. 2023

Preprint

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The MYC oncoprotein represents an intriguing target for cancer treatment, but its therapeutic potential has been hindered by the absence of specific pharmacological inhibitors. In this study, we demonstrate that the phenoxy quinoline compound LXY18 selectively targets and eliminates cells overexpressing MYC, leaving non-transformed cells unharmed. This synthetic lethality arises from an acute induction of multipolarity, resulting in a persistent arrest in early mitosis followed by cell death in mitosis or after mitotic slippage. Distinctively, LXY18’s action contrasts with other antimitotic compounds, as they either fail to induce mitotic arrest or elicit mitotic arrest irrespective of MYC abundance. Furthermore, the MYC abundance in a panel of 98 tumor cell lines correlates with their sensitivity to LXY18. Collectively, our findings uncover LXY18 as an MYC- enabled mitotic blocker and open a new avenue to selectively target MYC-overexpressing tumor cells without affecting normal cells.

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“…Its elimination inhibits the proliferation of IVD cells, revealing that CCNB1 is an important regulator of the G2/M phase of NP cells (35). Finally, Kinesin-like family member 20A (KIF20A), is considered as a significant molecule for cell cycle regulation (36). Zhao et al demonstrated that KIF20A can promote tumor cell proliferation and inhibit apoptosis in vivo and in vitro (37).…”

Section: Discussionmentioning

confidence: 99%

Macrophage polarization regulates intervertebral disc degeneration by modulating cell proliferation, inflammation mediator secretion, and extracellular matrix metabolism

Luo

et al. 2022

Front. Immunol.

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Macrophage infiltration and polarization have been increasingly observed in intervertebral disc (IVD) degeneration (IDD). However, their biological roles in IDD are still unrevealed. We harvested conditioned media (CM) derived from a spectrum of macrophages induced from THP-1 cells, and examined how they affect nucleus pulposus cells (NPCs) in vitro, by studying cell proliferation, extracellular matrix (ECM) synthesis, and pro-inflammation expression; and in vivo by injection CM in a rat IDD model. Then, high-throughput sequencing was used to detect differentially expressed genes (DEGs). Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) networks were used to further analysis. Higher CCR7+ (M1 marker) and CD206+ (M2 marker) cell counts were found in the degenerated human IVD tissues as compared with the control. Furthermore, the cell co-culture model showed M1CM attenuated NPC proliferation, downregulated the expression of ECM anabolic genes encoding aggrecan and collagen IIα1, upregulated the expression of ECM catabolic genes encoding MMP-13, and inflammation-related genes encoding IL-1β, IL-6, and IL-12, while M2CM showed contrasting trends. In IDD model, higher histological scores and lower disc height index were found following M1CM treatment, while M2CM exhibited opposite results. M1CM injection decreased ECM anabolic and increased ECM catabolic, as well as the upregulation of inflammation-related genes after 8 weeks treatment, while M2CM slowed down these trends. Finally, a total of 637 upregulated and 655 downregulated genes were detected in M1CM treated NPCs, and 975 upregulated genes and 930 downregulated genes in the M2CM groups. The top 30 GO terms were shown and the most significant KEGG pathway was cell cycle in both groups. Based on the PPI analysis, the five most significant hub genes were PLK1, KIF20A, RRM2, CDC20, and UBE2C in the M1CM groups and RRM2, CCNB1, CDC20, PLK1, and UBE2C in the M2CM groups. In conclusion, macrophage polarization exhibited diverse roles in IDD progression, with M1CM exacerbating cell proliferation suppression and IVD degeneration, while M2CM attenuated IDD development. These findings may facilitate the further elucidation of the role of macrophage polarization in IDD, and provide novel insights into the therapeutic potential of macrophages.

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MKLP2 functions in early mitosis to ensure proper chromosome congression

Cited by 6 publications

References 56 publications

Metochalcone induces senescence-associated secretory phenotype via JAK2/STAT3 pathway in breast cancer

Metochalcone induces senescence-associated secretory phenotype via JAK2/STAT3 pathway in breast cancer

MYC amplifies mitotic perturbations elicited by LXY18 to enable synthetic lethality

Macrophage polarization regulates intervertebral disc degeneration by modulating cell proliferation, inflammation mediator secretion, and extracellular matrix metabolism

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