Indisulam
exhibits antitumor activity against several cancer cells.
Although the DCAF15-indisulam-RBM39 axis has been well documented
in the inhibition of cancer cell growth, it is unknown whether RBM39
degradation alone is the mechanism of action of indisulam. Here, we
verified the inhibitory effect of indisulam on the proliferation of
gastric cancer cells and its dependence on DCAF15. Proximity-dependent
biotin labeling with TurboID and quantitative proteomics revealed
that indisulam indeed promoted the interaction between DCAF15 and
RBM39. Immunoblotting and immunofluorescence also revealed that indisulam
promoted the ubiquitin-mediated RBM39 degradation and RBM39 colocalized
with DCAF15 in the nucleus. DCAF15 knockdown almost completely abolished
the indisulam-mediated RBM39 reduction. Further knockdown of RBM39 eliminated the effect of DCAF15 on
the proliferation of gastric cancer cells upon indisulam treatment.
Immunoblotting of gastric tumor tissues confirmed the downregulation
of RBM39 by indisulam. Database analysis unveiled that RBM39 was highly expressed in gastric cancer tissues and its high expression
significantly shortened the survival time of gastric cancer patients.
Taken together, we demonstrated that indisulam enhanced RBM39 ubiquitination
and degradation by promoting its interaction with DCAF15, thus inhibiting
the proliferation of gastric cancer cells. This work may provide valuable
information for drug discovery through proteolysis targeting chimeras.
MS data were deposited in ProteomeXchange (Dataset identifier: PXD024168).
Ginsenoside Rg3, a natural compound, has been reported to function as an anticancer agent for hepatoma carcinoma, while the mechanisms underlying the anticancer effects are not clear. Therefore, the objective of our study was to explore the impact of RG3 on cell migration and invasion by regulating the lncRNA HOX antisense intergenic (HOTAIR) expression involving PI3K/ AKT signaling pathway. qRT-PCR was utilized to measure the mRNA expression of HOTAIR. Furthermore, HOTAIR overexpression plasmids were transfected to SMMC-7721 and SK-Hep-1 cells. Additionally, MTT assay was used to evaluate the proliferation of transfected cells. The scratch and transwell assays were used to determine the migration and invasion ability of the cell. The protein levels were determined with Western blot. lncRNA HOTAIR was overexpressed in SMMC-7721 and SK-Hep-1 cells. Ginsenoside-Rg3 reduced the level of lncRNA HOTAIR. Overexpressed lncRNA HOTAIR offset ginsenoside-Rg3 inhibited proliferation, migration and invasion of HCC cells. Furthermore, ginsenoside-Rg3 decreased the expression of p-AKT, p-PI3K, matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (MMP9), which was reversed after the treatment of HOTAIR. LncRNA HOTAIR was overexpressed in SMMC-7721 cells. Ginsenoside-Rg3 could reduce the expression of lncRNA HOTAIR, resulting in the inhibited cell proliferation, migration and invasion. Furthermore, ginsenoside-Rg3 inhibited cell proliferation and invasion ability through the PI3k/AKT pathway. Thus, ginsenoside-Rg3 might be a potential and effective treatment for HCC.
Non-small cell lung cancer (NSCLC) is a global burden leading to millions of deaths worldwide every year. Nanomedicine refers to the use of materials at the nanoscale for drug delivery and subsequent therapeutic approaches in cancer. Carbon nanotubes (CNTs) are widely used as nanocarriers for therapeutic molecules such as plasmids, siRNAs, antisense agents, aptamers and molecules related to the immunotherapy for several cancers. They are usually functionalized and loaded with standard drug molecules to improve their therapeutic efficiency. Functionalization and drug loading possibly decrease the genotoxic and carcinogenic potential of CNTs. In addition, the targeted cytotoxic properties of the drug improve and undesired toxicity decreases after drug loading and/or conjugation with proteins, including antibodies. For intended drug delivery, a lysosomal pH of 5.5 is more suitable and effective for the slow and extended release of cytotoxic drugs than a physiological of pH 7.4. Remarkably, CNTs possess intrinsic antitumor properties and are usually internalized by endocytosis. After being internalized, several mechanisms are involved in the therapeutic and carcinogenic effects of CNTs. They are generally safe for therapy, and their toxicity profile remains dependent on their physicochemical properties. Moreover, the dose, route, duration of exposure, surface properties and degradative potential determine the toxicity outcomes of CNTs locally or systemically. In summary, the use of CNTs in drug delivery and NSCLC therapy, as well as their genotoxic and carcinogenic potential and the possible mechanisms, has been discussed in this review. The therapeutic index is generally high for NSCLC cells treated with drug-loaded CNTs; therefore, they are effective carriers in implementing targeted therapy for NSCLC.
Purpose: To study the impact of matrine on cell cycle and apoptotic changes in hepatoma cells, and the mechanism involved.
Methods: Human hepatoma cell line HepG2 was treated with different concentrations of matrine. The blank control cells were maintained in 1640 medium only. The influence of matrine on proliferative ability was determined with 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT) method. Flow cytometry was used to determine its effect on cell cycle and apoptosis; RT-PCR (reverse transcription-polymerase chain reaction) was applied to assay the mRNA expressions of miR-122, cyclin G1 (CG1), livin and survivin mRNA, while the protein expressions of CG1, livin and surviving were assayed by Western blotting.
Results: Matrine time- and dose-dependently suppressed the proliferative capacity of the cells. At a concentration of 0.5 mg/mL, matrine had no significant effect on the cell cycle. However, 1.0 mg/mL matrine blocked the cell cycle in G1 phase, while 1.5 mg/mL matrine blocked HepG2 cells in G2/M phase (p < 0.05). Moreover, matrine induced apoptosis in HepG2 cells, and markedly downregulated the expressions of miR-122 concentration- time-reliantly (p < 0.05). In addition, matrine markedly and concentration-dependently reduced mRNA and protein expression levels of CG1, livin and survivin, with the strongest inhibitory effect at a level of 1.5 mg/mL.
Conclusion: Matrine induces cell cycle block and apoptotic changes in hepatoma cells through a mechanism related to regulation of the CG1/livin/survivin signal axis mediated by miR-122. Matrine may be a potential treatment for liver cancer. However, clinical trials are needed to confirm this potential.
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