Combination Antitumor Effect of Sorafenib via Calcium-Dependent Deactivation of Focal Adhesion Kinase Targeting Colorectal Cancer Cells

Jeong, Keun‐Yeong; Park, Min Hee; Sim, Jae-Jun; Kim, Hwan Mook

doi:10.3390/molecules25225299

Cited by 14 publications

(10 citation statements)

References 23 publications

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“…Recent studies based on the molecularly targeted drugs Bevacizumab, Cetuximab and Sorafenib have been used for treating CRC. These drugs have improved the overall survival rate of CRC patients ( Garcia et al, 2020 ; Jeong et al, 2020 ; Giordano et al, 2021 ). However, not all patients, especially the ones with advanced and distant metastases, benefit from these targeted drugs.…”

Section: Introductionmentioning

confidence: 99%

Bioinformatic Analyses and Experimental Verification Reveal that High FSTL3 Expression Promotes EMT via Fibronectin-1/α5β1 Interaction in Colorectal Cancer

Liu

Zeng

et al. 2021

Front. Mol. Biosci.

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Background: Colorectal cancer (CRC) is a typical cancer prevalent worldwide. Despite the conventional treatments, CRC has a poor prognosis due to relapse and metastasis. Moreover, there is a dearth of sensitive biomarkers for predicting prognosis in CRC.Methods: This study used a bioinformatics approach combining validation experiments to examine the value of follistatin-like 3 (FSTL3) as a prognostic predictor and therapeutic target in CRC.Results:FSTL3 was remarkably upregulated in the CRC samples. FSTL3 overexpression was significantly associated with a poor prognosis. FSTL3 was found to activate the epithelial-mesenchymal transition by promoting the binding of FN1 to α5β1. FSTL3 expression was also positively correlated with the abundance of the potent immunosuppressors, M2 macrophages.Conclusion:FSTL3 overexpression affects CRC prognosis and thus, FSTL3 can be a prognostic biomarker and therapeutic target with potential applications in CRC.

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Section: Introductionmentioning

confidence: 99%

Bioinformatic Analyses and Experimental Verification Reveal that High FSTL3 Expression Promotes EMT via Fibronectin-1/α5β1 Interaction in Colorectal Cancer

Liu

Zeng

et al. 2021

Front. Mol. Biosci.

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“…A previous study reported that maintained Ca 2+ influx can destroy the components of FAK’s focal connections in the presence of Src deficiency, markedly inhibiting cell invasion and motility ( Jeong et al, 2020 ). We further investigated whether RB altered intracellular Ca 2+ levels to suppress the Src/FAK/Paxillin focal adhesion pathway, thereby inhibiting the invasion of GBM cells.…”

Section: Resultsmentioning

confidence: 99%

Resibufogenin Targets the ATP1A1 Signaling Cascade to Induce G2/M Phase Arrest and Inhibit Invasion in Glioma

et al. 2022

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Resibufogenin (RB) is a major active ingredient in the traditional Chinese medicine Chansu and has garnered considerable attention for its efficacy in the treatment of cancer. However, the anticancer effects and underlying mechanisms of RB on glioblastoma (GBM) remain unknown. Here, we found that RB induced G2/M phase arrest and inhibited invasion in a primary GBM cell line, P3#GBM, and two GBM cell lines, U251 and A172. Subsequently, we demonstrated that RB-induced G2/M phase arrest occurred through downregulation of CDC25C and upregulation of p21, which was caused by activation of the MAPK/ERK pathway, and that RB inhibited GBM invasion by elevating intercellular Ca2+ to suppress the Src/FAK/Paxillin focal adhesion pathway. Intriguingly, we confirmed that upon RB binding to ATP1A1, Na+-K+-ATPase was activated as a receptor and then triggered the intracellular MAPK/ERK pathway and Ca2+-mediated Src/FAK/Paxillin focal adhesion pathway, which led to G2/M phase arrest and inhibited the invasion of GBM cells. Taken together, our findings reveal the antitumor mechanism of RB by targeting the ATP1A1 signaling cascade and two key signaling pathways and highlight the potential of RB as a new class of promising anticancer agents.

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“…There is strong evidence of calcium-dependent suppression of cancer cell proliferation and migration by So, which occurs due to deactivation of FAK (focal adhesion kinase) and inhibition of Akt signaling. For example, the addition of lactate calcium salt to colorectal cancer cells causes an increase in [Ca 2+ ] i , which correlates with the inhibition of the above signaling pathways [ 39 ]. The continuous influx of Ca 2+ ions into the cytosol is one of the mechanisms of apoptosis activation due to calcium-dependent activation of proteolytic and catabolic degradation enzymes (proteases and phosphatases) [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of the Cytotoxic Effect of a Complex of Selenium Nanoparticles Doped with Sorafenib, “Naked” Selenium Nanoparticles, and Sorafenib on Human Hepatocyte Carcinoma HepG2 Cells

Varlamova

Goltyaev

Simakin

et al. 2022

IJMS

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Despite the use of sorafenib as one of the most effective drugs for the treatment of liver cancer, its significant limitations remain—poor solubility, the need to use high doses with the ensuing complications on healthy tissues and organs, and the formation of cell resistance to the drug. At the same time, there is more and more convincing evidence of the anticancer effect of selenium-containing compounds and nanoparticles. The aim of this work was to develop a selenium–sorafenib nanocomplex and study the molecular mechanisms of its anticancer effect on human hepatocyte carcinoma cells, where nanoselenium is not only a sorafenib transporter, but also an active compound. We have created a selenium–sorafenib nanocomplex based on selenium nanoparticles with size 100 nm. Using vitality tests, fluorescence microscopy, and PCR analysis, it was possible to show that selenium nanoparticles, both by themselves and doped with sorafenib, have a pronounced pro-apoptotic effect on HepG2 cells with an efficiency many times greater than that of sorafenib (So). “Naked” selenium nanoparticles (SeNPs) and the selenium–sorafenib nanocomplex (SeSo), already after 24 h of exposure, lead to the induction of the early stages of apoptosis with the transition to the later stages with an increase in the incubation time up to 48 h. At the same time, sorafenib, at the studied concentrations, began to exert a proapoptotic effect only after 48 h. Under the action of SeNPs and SeSo, both classical pathways of apoptosis induction and ER-stress-dependent pathways involving Ca2+ ions are activated. Thus, sorafenib did not cause the generation of Ca2+ signals by HepG2 cells, while SeNPs and SeSo led to the activation of the Ca2+ signaling system of cells. At the same time, the selenium–sorafenib nanocomplex turned out to be more effective in activating the Ca2+ signaling system of cells, inducing apoptosis and ER stress by an average of 20–25% compared to “naked” selenium nanoparticles. Our data on the mechanisms of action and the created nanocomplex are promising as a platform for the creation of highly selective and effective drugs with targeted delivery to tumors.

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Combination Antitumor Effect of Sorafenib via Calcium-Dependent Deactivation of Focal Adhesion Kinase Targeting Colorectal Cancer Cells

Cited by 14 publications

References 23 publications

Bioinformatic Analyses and Experimental Verification Reveal that High FSTL3 Expression Promotes EMT via Fibronectin-1/α5β1 Interaction in Colorectal Cancer

Bioinformatic Analyses and Experimental Verification Reveal that High FSTL3 Expression Promotes EMT via Fibronectin-1/α5β1 Interaction in Colorectal Cancer

Resibufogenin Targets the ATP1A1 Signaling Cascade to Induce G2/M Phase Arrest and Inhibit Invasion in Glioma

Comparative Analysis of the Cytotoxic Effect of a Complex of Selenium Nanoparticles Doped with Sorafenib, “Naked” Selenium Nanoparticles, and Sorafenib on Human Hepatocyte Carcinoma HepG2 Cells

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