FRMD8 targets both CDK4 activation and RB degradation to suppress colon cancer growth

Yu, Miao; Wu, Weijie; Sun, Yi; Yan, Haoyi; Zhang, Lei; Wang, Zhenbin; Gong, Yuqing; Wang, Tianzhuo; Li, Qianchen; Song, Jiagui; Wang, Mengyuan; Zhang, Jing; Tang, Yan; Zhan, Jun; Zhang, Hongquan

doi:10.1016/j.celrep.2023.112886

Cited by 6 publications

(2 citation statements)

References 73 publications

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“…33,34 Previous reports showed that therapeutic agents arrest cells in G1-phase of the cell cycle by decreasing CDK4 and CCND1 levels in colon cancer cells. 15,35 Moreover, Constitutive activation of JAK2-STAT3 pathway has also been positively linked with the increased CDK4 and CCND1 levels in cancer cells. 5,7,15 In consistent with the previous studies that JAK2-STAT3 standard inhibitors (SAR317461, CYT387, pacritinib, and AG490) inhibit the phosphorylation of JAK2-STAT3 in tumor and their derived tumorspheres.…”

Section: Xiong Et Al Reported That Pharmacological Inhibition Of Jak2/mentioning

confidence: 99%

Kurarinone targets JAK2‐STAT3 signaling in colon cancer‐stem‐like cells

Prajapati,

Kumar

2024

Cell Biochemistry & Function

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Natural compounds are known to regulate stemness/self‐renewal properties in colon cancer cells at molecular level. In the present study, we first time studied the colon cancer stem‐like cells targeting potential of Kurarinone (KU) and explored the underlying mechanism. Cytotoxic potential of KU was checked in colon cancer cells. Colonosphere formation assay was performed to check the spheroid formation reduction potential of KU in HCT‐116 cells by using phase‐contrast microscopy. Stemness/self‐renewal marker expression was studied at mRNA and protein levels in colonosphere. The qRT‐PCR, western blot analysis, and flow cytometer techniques were used to assess the effect of KU treatment on cell cycle progression and apoptosis induction in colon cancer cells and colonosphere. Further, effect of KU treatment on pSTAT3 status and its nuclear translocation was also studied. KU treatment significantly decreased HCT‐116 cell proliferation and reduced sphere formation potential at IC30 (8.71 µM) and IC50 (20.34 µM) concentrations compared to respective vehicle‐treated groups, respectively. KU exposure significantly reduced the expression of CD44, c‐Myc, Bmi‐1, and Sox2 stemness/self‐renewal markers in colonosphere in a dose‐dependent manner. KU treatment inhibits JAK2‐STAT3 signaling pathway by reducing pSTAT3 levels and its nuclear translocation in HCT‐116 cells and colonosphere at IC50 concentration. KU treatment significantly decreased the expression of CCND1 and CDK4 cell cycle‐specific markers and arrested the HCT‐116 cells and colonosphere in G1‐phase. Further, KU treatment increased Bax/Bcl‐2 ratio, apoptotic cell population, cleaved caspase 3, and PARP‐1 in HCT‐116 cells and colonosphere. In conclusion, KU treatment decreases stemness/self‐renewal, induces cell cycle arrest and apoptosis in HCT‐116 colonosphere by down‐regulating CD44‐JAK2‐STAT3 axis. Thus, targeting stemness/self‐renewal and other cancer hallmark(s) by KU through CD44/JAK2/STAT3 signaling pathway might be a novel strategy to target colon cancer stem‐like cells.

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Section: Xiong Et Al Reported That Pharmacological Inhibition Of Jak2/mentioning

confidence: 99%

Kurarinone targets JAK2‐STAT3 signaling in colon cancer‐stem‐like cells

Prajapati,

Kumar

2024

Cell Biochemistry & Function

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“…Among these, cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) are pivotal in mediating the transition of cells into the S phase, essential for the initiation, growth, and maintenance of numerous cancer types [ 20 ]. This process is predominantly driven by the Cyclin D-CDK4/6 complex [ 21 ], with studies indicating that abnormalities in both CDK4 [ 22 ] and CCND1 (Cyclin D1) [ 23 ] are linked to CRC. When the levels of D-type cyclins increase, CDK4 can form a complex with CCND1 and p27 protein, thereby facilitating the phosphorylation of retinoblastoma tumor suppressor protein (Rb) and other substrates [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Mapping alternative splicing events in colorectal cancer

Zheng,

Zhong,

Song

et al. 2024

Discov Onc

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Although aberrant splicing events of genes are closely related to the development and progression of colorectal cancer (CRC), the mapping of abnormal splicing events, especially alternative splicing (AS) event types and the underlying effects, remain investigational. In the present study, we analyzed a public RNA-seq database (GSE138202) and identified 14,314 significant AS events in CRC patients compared to healthy individuals. Most of the key genes such as oncogenes involved in the development of CRC have different AS event types. Moreover, the results demonstrate that certain AS events may play a significant role in the functioning of key genes involved in splicing factors and microRNAs. Furthermore, we observed that the oncogene CDK4 in CRC tends to undergo exon 2 skipping AS events, resulting in a stronger tendency for protein expression to form complexes with CCND1, thereby inhibiting the cell cycle and weakening cell proliferation, while enhancing cell migration capability. These findings not only provide new insights into the mechanism of AS in regulating CRC, but also offers a theoretical basis for targeted splicing therapy in CRC.

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