Skp2 inhibitor SKPin C1 decreased viability and proliferation of multiple myeloma cells and induced apoptosis

Yan, Wei; Liu, Zhuogang; Wei, Minjie

doi:10.1590/1414-431x20198412

Cited by 10 publications

(5 citation statements)

References 19 publications

(31 reference statements)

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“…This mild discrepancy could be attributed to the different laboratory technique (Western blot assay), which was not applied in the present study. It is interesting to note that SKP2 overexpression was observed in multiple solid tumors as well as hematological malignancies [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. Importantly, the results obtained from the present study revealed that the expression levels of SKP2 were significantly higher in the CML patients with warning/failure responses to IM treatment compared to the CML patients with optimal responses at the early response stage.…”

Section: Discussionmentioning

confidence: 99%

“…SKP2 mostly functions as an oncoprotein, and is involved in cell proliferation, migration, invasion, angiogenesis, apoptosis, and metastasis [ 28 ]. In addition, SKP2 overexpression was observed in several human malignancies, such as breast cancer, non-small-cell lung cancer, pancreatic cancer, gastric cancer, prostate cancer, melanoma, and hematological malignancies [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. Importantly, SKP2 has been identified in CML progression.…”

Section: Introductionmentioning

confidence: 99%

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The Impact of SKP2 Gene Expression in Chronic Myeloid Leukemia

Hodeib

Hai

Tawfik

et al. 2022

Genes

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Introduction: The prognosis of chronic myeloid leukemia (CML) patients has been dramatically improved with the introduction of imatinib (IM), the first tyrosine kinase inhibitor (TKI). TKI resistance is a serious problem in IM-based therapy. The human S-phase kinase-associated protein 2 (SKP2) gene may play an essential role in the genesis and progression of CML. Aim of the study: We try to explore the diagnostic/prognostic impact of SKP2 gene expression to predict treatment response in first-line IM-treated CML patients at an early response stage. Patients and methods: The gene expression and protein levels of SKP2 were determined using quantitative RT-PCR and ELISA in 100 newly diagnosed CML patients and 100 healthy subjects. Results: SKP2 gene expression and SKP2 protein levels were significantly upregulated in CML patients compared to the control group. The receiver operating characteristic (ROC) analysis for the SKP2 gene expression level, which that differentiated the CML patients from the healthy subjects, yielded a sensitivity of 86.0% and a specificity of 82.0%, with an area under the curve (AUC) of 0.958 (p < 0.001). The ROC analysis for the SKP2 gene expression level, which differentiated optimally from the warning/failure responses, yielded a sensitivity of 70.59% and a specificity of 71.21%, with an AUC of 0.815 (p < 0.001). Conclusion: The SKP2 gene could be an additional diagnostic and an independent prognostic marker for predicting treatment responses in first-line IM-treated CML patients at an early time point (3 months).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Impact of SKP2 Gene Expression in Chronic Myeloid Leukemia

Hodeib

Hai

Tawfik

et al. 2022

Genes

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“…SKPin C1 has also been reported to inhibit uveal melanoma and lung cancer growth both in vitro and in vivo ( Zhao et al, 2020 ) ( Zhao et al, 2019 ) ( Table 2 ); trigger cell apoptosis in metastatic melanoma and breast cancer in vitro ; and inhibit proliferation of murine primary T-ALL cells with wildtype Skp2, as well as several human T-ALL cell lines ( Rodriguez et al, 2020 ) ( Table 2 ). In addition, SKPin C1 has also been reported to inhibit cell proliferation in U266 and RPMI 8226 myeloma cells and to trigger apoptosis by increasing cleaved caspase-3 protein levels ( Yang et al, 2019 ). However, SKPin C1 does not inhibit the proliferation of SKP2 knock-out embryonic fibroblasts ( Rodriguez et al, 2020 ).…”

Section: Synthetic Small-molecule Skp2-inhibiting Compoundsmentioning

confidence: 99%

Small-molecule compounds inhibiting S-phase kinase-associated protein 2: A review

et al. 2023

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S-phase kinase-associated protein 2 (Skp2) is a substrate-specific adaptor in Skp1-CUL1-ROC1-F-box E3 ubiquitin ligases and widely regarded as an oncogene. Therefore, Skp2 has remained as an active anticancer research topic since its discovery. Accordingly, the structure of Skp2 has been solved and numerous Skp2 inhibiting compounds have been identified. In this review, we would describe the structural features of Skp2, introduce the ubiquitination function of SCFSkp2, and summarize the diverse natural and synthetic Skp2 inhibiting compounds reported to date. The IC50 data of the Skp2 inhibitors or inhibiting compounds in various kinds of tumors at cellular levels implied that the cancer type, stage and pathological mechanisms should be taken into consideration when selecting Skp2-inhibiting compound for cancer treatment.

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“…MLN4924, a NEDD8 inhibitor, served as a non-specific reference control, and the concentrations were used as reported [24]. The concentrations of SKPin C1, CC220, clomipramine, or CPZ used herein were based on previous reports [25][26][27][28][29]. The resulting lysates were subjected to western analyses.…”

Section: Downregulation Of Jak1 By Ag1024 Induced Proteolysis Was Med...mentioning

confidence: 99%

Tyrphostin AG1024 Suppresses Coronaviral Replication by Downregulating JAK1 via an IR/IGF-1R Independent Proteolysis Mediated by Ndfip1/2_NEDD4-like E3 Ligase Itch

et al. 2022

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JAK1 depletion or downregulation was previously reported to account for coronavirus inhibition. Here, we found that AG1024, an IR (insulin receptor) and IGF-1R (insulin-like growth factor 1 receptor) inhibitor, diminishes JAK1 protein levels and exerts anti-coronaviral activities with EC50 values of 5.2 ± 0.3 μM against transmissible gastroenteritis coronavirus (TGEV) and 4.3 ± 0.3 μM against human flu coronavirus OC43. However, although the IR and IGF-1R signaling pathways are activated by insulin or IGF-1 in swine testis cells, they are not triggered upon TGEV infection. AG1024, therefore, inhibits coronaviral replication and downregulates JAK1 protein levels independently of IR and IGF-1R. Moreover, JAK1 proteolysis caused by AG1024 was found through activation of upstream Ndfip1/2 and its effector NEDD4-like E3 ligase Itch. In addition, ouabain, which was reported to mediate JAK1 proteolysis causing anti-coronaviral activity by activation of Ndfip1/2 and NEDD4 E3 ligase, additively inhibited anti-coronaviral activity and JAK1 diminishment in combination with AG1024. This study provides novel insights into the pharmacological effects of AG1024 and Itch E3 ligase mediated JAK1 proteolysis and identified Ndfip1/2 as a cognate effector for JAK1 proteolysis via the diversified E3 ligases NEDD4 and NEDD4-like Itch. These findings are expected to provide valued information for the future development of anti-viral agents.

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Skp2 inhibitor SKPin C1 decreased viability and proliferation of multiple myeloma cells and induced apoptosis

Cited by 10 publications

References 19 publications

The Impact of SKP2 Gene Expression in Chronic Myeloid Leukemia

The Impact of SKP2 Gene Expression in Chronic Myeloid Leukemia

Small-molecule compounds inhibiting S-phase kinase-associated protein 2: A review

Tyrphostin AG1024 Suppresses Coronaviral Replication by Downregulating JAK1 via an IR/IGF-1R Independent Proteolysis Mediated by Ndfip1/2_NEDD4-like E3 Ligase Itch

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