Imatinib and GNF-5 Exhibit an Inhibitory Effect on Growth of Hepatocellar Carcinoma Cells by Downregulating S-phase Kinase-associated Protein 2

Zhang, Haibo; Yi, Jun Koo; Yoon, Duhak; Ryoo, Zae-Young; Lee, Inkyu; Kim, Myoungok

doi:10.15430/jcp.2020.25.4.252

Cited by 6 publications

(3 citation statements)

References 24 publications

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“…Furthermore, a fraction of primary GISTs that do not respond to IM by apoptosis are eliminated from the proliferative pool by entering quiescence via the modulation of the anaphase-promoting complex (APC)/CDH1-SKP2-p27 Kip1 signaling axis. Moreover, Zhang et al [ 61 ] reported that IM and GNF-5 inhibited hepatocellular carcinoma (HCC) cell growth via the downregulation of SKP2 expression and the upregulation of both p27 and p21 levels in HepG2 cells, inducing G0/G1 phase cell-cycle arrest. In brief, our results confirmed and extended prior reports clarifying the in vitro cellular response to IM in different malignancies in general and CML in particular.…”

Section: Discussionmentioning

confidence: 99%

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%

The Impact of SKP2 Gene Expression in Chronic Myeloid Leukemia

Hodeib

Hai

Tawfik

et al. 2022

Genes

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“…Imatinib is a tyrosine kinase inhibitor and impairs HCC cell metastasis by increasing NM23 expression (199). To improve the anti-cancer activity of imatinib against HCC, attempts have been made to combine it with other antitumor agents such as sulfasalazine and GNF-5 [200,201]. Moreover, incorporation of imatinib into lactoferrin-modified PEGylated liquid crystalline nanostructures induces apoptosis in HCC via the mitochondrial pathway [202].…”

Section: Synthetic Drugsmentioning

confidence: 99%

Targeting and regulation of autophagy in hepatocellular carcinoma: revisiting the molecular interactions and mechanisms for new therapy approaches

et al. 2023

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Autophagy is an evolutionarily conserved process that plays a role in regulating homeostasis under physiological conditions. However, dysregulation of autophagy is observed in the development of human diseases, especially cancer. Autophagy has reciprocal functions in cancer and may be responsible for either survival or death. Hepatocellular carcinoma (HCC) is one of the most lethal and common malignancies of the liver, and smoking, infection, and alcohol consumption can lead to its development. Genetic mutations and alterations in molecular processes can exacerbate the progression of HCC. The function of autophagy in HCC is controversial and may be both tumor suppressive and tumor promoting. Activation of autophagy may affect apoptosis in HCC and is a regulator of proliferation and glucose metabolism. Induction of autophagy may promote tumor metastasis via induction of EMT. In addition, autophagy is a regulator of stem cell formation in HCC, and pro-survival autophagy leads to cancer cell resistance to chemotherapy and radiotherapy. Targeting autophagy impairs growth and metastasis in HCC and improves tumor cell response to therapy. Of note, a large number of signaling pathways such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs regulate autophagy in HCC. Moreover, regulation of autophagy (induction or inhibition) by antitumor agents could be suggested for effective treatment of HCC. In this paper, we comprehensively review the role and mechanisms of autophagy in HCC and discuss the potential benefit of targeting this process in the treatment of the cancer. Graphical abstract

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“…Bcr-Abl recruits p300 to the Sp1 site of SKP2 promoter, up-regulating Skp2 mRNA expression, and Imatinib inhibits this recruitment, leading to decreased Skp2 mRNA. Recently, treatment with Imatinib and GNF-5 has been reported to suppress the expression of Skp2 ( Chen et al, 2009 ), and induce G0/G1 cell cycle arrest, increase p27 and p21 protein levels, inhibiting cell growth in hepatocellular carcinoma (HCC) ( Zhang et al, 2020 ), implying that these two drugs could be used as a potential Skp2-inhibiting compounds indirectly. However, further work is needed to explain the mechanisms of these two TKIs.…”

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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Imatinib and GNF-5 Exhibit an Inhibitory Effect on Growth of Hepatocellar Carcinoma Cells by Downregulating S-phase Kinase-associated Protein 2

Cited by 6 publications

References 24 publications

The Impact of SKP2 Gene Expression in Chronic Myeloid Leukemia

The Impact of SKP2 Gene Expression in Chronic Myeloid Leukemia

Targeting and regulation of autophagy in hepatocellular carcinoma: revisiting the molecular interactions and mechanisms for new therapy approaches

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

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