A therapeutic trial of human melanomas with combined small interfering RNAs targeting adaptor molecules p130Cas and paxillin activated under expression of ganglioside GD3

Makino, Yusuke; Hamamura, Kazunori; Takei, Yoshiyuki; Bhuiyan, Robiul H.; Ohkawa, Yuki; Ohmi, Yuhsuke; Nakashima, Hideyuki; Furukawa, Koichi

doi:10.1016/j.bbagen.2016.04.005

Cited by 14 publications

(10 citation statements)

References 58 publications

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“…However, targeting paxillin with siRNA has had limited effect on suppressing tumor growth in vivo. 38 These results suggest that cyclin F is involved in signal transduction between ECM and cell, which may at least in part be related to higher levels of paxillin and vimentin. Vimentin is an intermediate filament stabilizing the actin cytoskeleton and is an established EMT marker.…”

Section: Discussionmentioning

confidence: 83%

Cyclin F Downregulation Affects Epithelial-Mesenchymal Transition Increasing Proliferation and Migration of the A-375 Melanoma Cell Line

Krajewski¹,

Gagat²,

Mikołajczyk³

et al. 2020

CMAR

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Background Cyclins are well-known cell cycle regulators. The activation of cyclin-dependent kinases by cyclins allows orchestration of the complicated cell cycle machinery and drives the cell from the G1 phase to the end of the mitotic phase. In recent years, it has become evident that cyclins are involved in processes beyond the cell cycle. Cyclin F does not activate CDKs but forms part of the Skp1-Cul1-F-box (SCF) complex where it is responsible for protein target recognition and subsequent degradation in a proteasome-dependent manner. Results Here, we report that the downregulation of cyclin F in the A-375 melanoma cell line increases cell viability and colony formation in a cell cycle independent manner. Lower levels of cyclin F do not appear to affect the cell cycle, based on flow cytometry measuring BrdU incorporation and propidium iodide staining. By means of immunofluorescence staining and Western blot analysis, we observed changes in cell morphology-related markers which suggested ongoing epithelial-mesenchymal transition (EMT) in response to cyclin F downregulation. Increases in vimentin and N-cadherin protein levels, decreases in levels of epithelial markers such as ZO-1, along with changes in morphology to a spindle-like shape with the appearance of actin stress fibers, are all hallmarks of EMT. These changes are associated with increased invasive and migratory potential, based on 2D migration assays. Moreover, we observe an increase in RhoABC, talin and paxillin levels, the proteins involved in controlling cell signaling and motility. Lastly, upon knocking down cyclin F expression, we observed a decrease in thrombospondin-1 expression, suggesting a role of cyclin F in angiogenesis. Conclusion Cyclin F depletion induces proliferation and EMT processes in the A-375 melanoma model.

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Section: Discussionmentioning

confidence: 83%

Cyclin F Downregulation Affects Epithelial-Mesenchymal Transition Increasing Proliferation and Migration of the A-375 Melanoma Cell Line

Krajewski¹,

Gagat²,

Mikołajczyk³

et al. 2020

CMAR

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“…For example, when a novel signaling pathway activated by cancer‐associated glycosphingolipids is found, key molecules in the pathway could be targets of therapy. In fact, p130Cas and paxillin, which are activated in GD3 + melanomas, were examined as possible target molecules for siRNA therapy . Membrane proteins that are identified as partners of cancer‐associated glycolipids might be better targets for treatment.…”

Section: Development Of Novel Technology Enables Us To Further Undersmentioning

confidence: 99%

“…In fact, p130Cas and paxillin, which are activated in GD3 + melanomas, were examined as possible target molecules for siRNA therapy. 55 Membrane proteins that are identified as partners of cancer-associated glycolipids might be better targets for treatment.…”

Section: De Velopment Of Novel Technology Enab Le S Us To Further Umentioning

confidence: 99%

New era of research on cancer‐associated glycosphingolipids

et al. 2019

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Cancer‐associated glycosphingolipids have been used as markers for diagnosis and targets for immunotherapy of malignant tumors. Recent progress in the analysis of their implications in the malignant properties of cancer cells revealed that cancer‐associated glycosphingolipids are not only tumor markers, but also functional molecules regulating various signals introduced by membrane microdomains, lipid rafts. In particular, a novel approach, enzyme‐mediated activation of radical sources combined with mass spectrometry, has enabled us to clarify the mechanisms by which cancer‐associated glycosphingolipids regulate cell signals based on the interaction with membrane molecules and formation of molecular complexes on the cell surface. Novel findings obtained from these approaches are now providing us with insights into the development of new anticancer therapies targeting membrane molecular complexes consisting of cancer‐associated glycolipids and their associated membrane molecules. Thus, a new era of cancer‐associated glycosphingolipids has now begun.

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“…However, some of these treatments are over time met with resistance. In efforts to circumvent this problem, several groups have started to develop inhibitors targeting adaptor proteins instead, for instance by downregulating BCAR1 in the tumour 138 . Similarly, both the SH2 domains of GRB2 and NCK1, which are implicated in several cancers, have been suggested as targets for cancer therapies 58,139,140 …”

Section: Adaptor Proteins In Human Diseasementioning

confidence: 99%