Inhibition of Vav3 could reverse the drug resistance of gastric cancer cells by downregulating JNK signaling pathway

Tan, Bibo; Li, Y; Zhao, Qun; Fan, Li; Liu, Y; Wang, D; Zhao, Xuefeng

doi:10.1038/cgt.2014.59

Cited by 13 publications

(10 citation statements)

References 39 publications

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“…Therefore, we speculate that LXR623 kills tumour cells by promoting cholesterol efflux and inhibiting cholesterol influx. We also found other upregulated or downregulated genes related to cell proliferation, invasion and metastasis, such as VAV3, CDH17, MMP1 and MMP13 33,34 . It can be speculated that LXR agonists and inverse agonists act on tumour cells in different ways, causing decreases in intracellular FA and cholesterol contents to inhibit tumour cells ( Fig.…”

Section: Sr9243 and Lxr623 Kill Ccrcc Cells Through Different Mechanismsmentioning

confidence: 60%

Targeting the transcription factor receptor LXR to treat clear cell renal cell carcinoma: agonist or inverse agonist?

Wang

et al. 2019

Cell Death Dis

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Growing evidence indicates that clear cell renal cell carcinoma (ccRCC) is a metabolism-related disease. Changes in fatty acid (FA) and cholesterol metabolism play important roles in ccRCC development. As a nuclear transcription factor receptor, Liver X receptor (LXR) regulates a variety of key molecules associated with FA synthesis and cholesterol transport. Therefore, targeting LXR may provide new therapeutic targets for ccRCC. However, the potential regulatory effect and molecular mechanisms of LXR in ccRCC remain unknown. In the present study, we found that both an LXR agonist and an XLR inverse agonist could inhibit proliferation and colony formation and induce apoptosis in ccRCC cells. We observed that the LXR agonist LXR623 downregulated the expression of the low-density lipoprotein receptor (LDLR) and upregulated the expression of ABCA1, which resulted in reduced intracellular cholesterol and apoptosis. The LXR inverse agonist SR9243 downregulated the FA synthesis proteins sterol regulatory element-binding protein 1c (SREBP-1c), fatty acid synthase (FASN) and stearoyl-coA desaturase 1 (SCD1), causing a decrease in intracellular FA content and inducing apoptosis in ccRCC cells. SR9243 and LXR623 induced apoptosis in ccRCC cells but had no killing effect on normal renal tubular epithelial HK2 cells. We also found that SRB1-mediated high-density lipoprotein (HDL) in cholesterol influx is the cause of high cholesterol in ccRCC cells. In conclusion, our data suggest that an LXR inverse agonist and LXR agonist decrease the intracellular FA and cholesterol contents in ccRCC to inhibit tumour cells but do not have cytotoxic effects on non-malignant cells. Thus, LXR may be a safe therapeutic target for treating ccRCC patients.

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Section: Sr9243 and Lxr623 Kill Ccrcc Cells Through Different Mechanismsmentioning

confidence: 60%

Targeting the transcription factor receptor LXR to treat clear cell renal cell carcinoma: agonist or inverse agonist?

Wang

et al. 2019

Cell Death Dis

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“…Moreover, the overexpression of multidrug resistance proteins by tumor cells causes efflux of various chemotherapeutic drugs. [5][6][7] Therefore, new chemotherapeutic agents are sorely needed.…”

Section: Introductionmentioning

confidence: 99%

Biodegradable micelles enhance the antiglioma activity of curcumin in vitro and in vivo

Zheng

Gao

Liu

et al. 2016

IJN

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Curcumin (Cur), a natural polyphenol of Curcuma longa , has been recently reported to possess antitumor activities. However, due to its poor aqueous solubility and low biological availability, the clinical application of Cur is quite limited. The encapsulation of hydrophobic drugs into nanoparticles is an effective way to improve their pharmaceutical activities. In this research, nanomicelles loaded with Cur were formulated by a self-assembly method with biodegradable monomethoxy poly(ethylene glycol)-poly(lactide) copolymers (MPEG-PLAs). After encapsulation, the cellular uptake was increased and Cur could be released from MPEG-PLA micelles in a sustained manner. The Cur-loaded MPEG-PLA micelles (Cur/MPEG-PLA micelles) exhibited an enhanced toxicity on C6 and U251 glioma cells and induced more apoptosis on C6 glioma cells compared with free Cur. Moreover, the therapy efficiency of Cur/MPEG-PLA micelles was evaluated at length on a nude mouse model bearing glioma. The Cur/MPEG-PLA micelles were more effective on suppressing tumor growth compared with free Cur, which indicated that Cur/MPEG-PLA micelles improved the antiglioma activity of Cur in vivo. The results of immunohistochemical and immunofluorescent analysis indicated that the induction of apoptosis, antiangiogenesis, and inhibition of cell proliferation may contribute to the improvement in antiglioma effects. Our data suggested that Cur/MPEG-PLA may have potential clinic applications in glioma therapy.

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“…47 In addition, siRNA-based downregulation of Vav3 yields a significant decrease in MDR1/P-gp, GST-p, Bcl-2 and Bax expression in gastric cancer cells. 50 In conclusion, we herein demonstrate for the first time that truncated Vav3.1 and not full-length isoform of Vav3, is clinically relevant in the pathophysiology of ovarian cancer. Importantly, Vav3.1 also appears to be decisively involved in mechanisms causing intrinsic drug resistance.…”

Section: Increased Vav31 Expression In Platinum-refractory Patientsmentioning

confidence: 51%

“…Recent data showed that knock‐down of Vav3 sensitizes paclitaxel (PTX)‐resistant cancer cells to PTX treatment . In addition, siRNA‐based downregulation of Vav3 yields a significant decrease in MDR1/P‐gp, GST‐π, Bcl‐2 and Bax expression in gastric cancer cells …”

Section: Discussionmentioning

confidence: 99%

Truncated isoform Vav3.1 is highly expressed in ovarian cancer stem cells and clinically relevant in predicting prognosis and platinum‐response

Reimer

Boesch

Wolf

et al. 2017

Intl Journal of Cancer

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Vav3 is a key modulator of GTP-hydrolases of the Rho/Rac family, which are crucially involved in cell proliferation. Vav3 is alternatively spliced in full-length Vav3-alpha and N-terminal truncated Vav3.1 lacking its self-regulatory domains. The aim of our study was to estimate the clinical impact of Vav3 and all other Vav family members in ovarian cancer. Purification of a stem-cell like side-population (SP) from ovarian cancer cell lines was performed by flow cytometry/FACS. Differences in gene expression between SP and NSP were assessed by Gene Array analysis and confirmed by RT-PCR and immunoblot. In addition, Vav mRNA expression was determined in 150 epithelial ovarian cancers. Clinicopathological parameters, platinum-sensitivity and survival were analyzed and associated with Vav expression. SP fractions of ovarian cancer cell lines exhibited marked overexpression of Vav3.1 (p < 0.001). Vav1 and Vav2 did not prove to be of clinicopathologic relevance in ovarian cancer. High Vav3.1 expression correlated with higher FIGO stage and residual disease. Furthermore, Vav3.1 overexpression was associated with poor progression-free (HR = 2.820, p = 0.0001) and overall survival (HR = 2.842, p = 0.0001). Subgroup analyses revealed an impact of Vav3.1 on survival in Type-II but not in Type-I cancers. Notably, platinum-refractory cancers showed marked overexpression of Vav3.1 compared to other subsets of platinum-sensitivity (15.848 vs. 6.653, p = 0.0001). In conclusion, Vav3.1 is over-expressed in stem-cell like SP fractions and is clinically relevant in the pathophysiology of ovarian cancer. The N-terminal truncated Vav3.1 may be decisively involved in mechanisms causing genuine multi-drug resistance.

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Inhibition of Vav3 could reverse the drug resistance of gastric cancer cells by downregulating JNK signaling pathway

Cited by 13 publications

References 39 publications

Targeting the transcription factor receptor LXR to treat clear cell renal cell carcinoma: agonist or inverse agonist?

Targeting the transcription factor receptor LXR to treat clear cell renal cell carcinoma: agonist or inverse agonist?

Biodegradable micelles enhance the antiglioma activity of curcumin in vitro and in vivo

Truncated isoform Vav3.1 is highly expressed in ovarian cancer stem cells and clinically relevant in predicting prognosis and platinum‐response

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