STAT3 interacts with Skp2/p27/p21 pathway to regulate the motility and invasion of gastric cancer cells

Wei, Zheng; Jiang, Xian; Qiao, Haiquan; Zhai, Bo; Zhang, Lianfeng; Zhang, Qiang; Wu, Yunxin; Jiang, Hongchi; Sun, Xueying

doi:10.1016/j.cellsig.2013.01.011

Cited by 105 publications

(86 citation statements)

References 34 publications

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“…Cell viability analysis, in vitro apoptosis assay, visualization of apoptotic cells by laser scanning confocal microscopy, assessment of Ki-67 proliferation index, in situ detection of apoptotic cell, and immunoblotting All these methods have been described in details previously (24)(25)(26).…”

Section: Animal Experimentsmentioning

confidence: 99%

Inhibition of Akt Reverses the Acquired Resistance to Sorafenib by Switching Protective Autophagy to Autophagic Cell Death in Hepatocellular Carcinoma

Zhai

Jiang

et al. 2014

Molecular Cancer Therapeutics

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Sorafenib is the standard first-line systemic drug for advanced hepatocellular carcinoma (HCC), but the acquired resistance to sorafenib results in limited benefits. Activation of Akt is thought to be responsible for mediating the acquired resistance to sorafenib. The present study aims to examine the underlying mechanism and seek potential strategies to reverse this resistance. Two sorafenib-resistant HCC cell lines, which had been established from human HCC HepG2 and Huh7 cells, were refractory to sorafenib-induced growth inhibition and apoptosis in vitro and in vivo. Sustained exposure to sorafenib activated Akt via the feedback loop of mTOR but independent of protein phosphatase 2A in HCC cells. Autophagy participated in the resistance to sorafenib as inhibition of autophagy reduced the sensitivity of sorafenib-resistant HCC cells to sorafenib, whereas activation of autophagy by rapamycin had the opposite effect. However, rapamycin did not show a synergistic effect with sorafenib to inhibit cell proliferation, while it also activated Akt via a feedback mechanism in sorafenib-resistant HCC cells. Inhibition of Akt reversed the acquired resistance to sorafenib by switching autophagy from a cytoprotective role to a death-promoting mechanism in the sorafenib-resistant HCC cells. Akt inhibition by GDC0068 synergized with sorafenib to suppress the growth of sorafenib-resistant HCC tumors that possessed the sorafenib-resistant feature in vivo. The results have provided evidence for clinical investigation of GDC0068, a novel ATP-competitive pan-Akt inhibitor, as the second-line treatment after the failure of sorafenib-medicated molecular targeted therapy for advanced HCC. Mol Cancer Ther; 13(6); 1589-98. Ó2014 AACR.

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Section: Animal Experimentsmentioning

confidence: 99%

Inhibition of Akt Reverses the Acquired Resistance to Sorafenib by Switching Protective Autophagy to Autophagic Cell Death in Hepatocellular Carcinoma

Zhai

Jiang

et al. 2014

Molecular Cancer Therapeutics

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237

234

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“…STAT3 plays a critical role in transcriptional regulation of genes and is also activated by many cytokines and growth factor receptors, such as PDGFR, fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR) through JAK [25,26] . The negative regulation of STAT3 is mainly executed by suppression of cytokine signaling (SOCS) proteins through JAK and Src-homology protein tyrosine phosphatases (SHPs), such as SHP-1 and SHP-2, and cytokines and growth factor receptors [23] .…”

Section: Jak-stat Pathway and Sorafenib Resistancementioning

confidence: 99%

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Zhai

Sun²

2013

WJH

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Sorafenib, the unique drug as first-line treatment for advanced hepatocellular carcinoma (HCC), has opened a window of hope after searching for effective agents to combat HCC for decades. However, the overall outcomes are far from satisfactory. One of the explanations is the genetic heterogeneity of HCC, which has led to identifying predictive biomarkers for primary resistance to sorafenib, and then applying the concept of personalized medicine, or seeking therapeutic strategies such as combining sorafenib with other anticancer agents. Some of the combinations have demonstrated a better effectiveness than sorafenib alone, with good tolerance. The acquired resistance to sorafenib has also drawn attention. As a multikinase inhibitor, sorafenib targets several cellular signaling pathways but simultaneously or sequentially the addiction switches and compensatory pathways are activated. Several mechanisms are involved in the acquired resistance to sorafenib, such as crosstalks involving PI3K/Akt and JAK-STAT pathways, hypoxia-inducible pathways, epithelial-mesenchymal transition, etc . Based on the investigated mechanisms, some other molecular targeted drugs have been applied as second-line treatment for treat HCC after the failure of sorafenib therapy and more are under evaluation in clinical trials. However, the exact mechanisms accounting for sorafenib resistance remains unclear. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms and help to find effective strategies for overcoming sorafenib resistance in HCC. Core tip: The primary resistance of hepatocellular carcinoma (HCC) to sorafenib is due to genetic heterogeneity. Thus, seeking predictive biomarkers and combining sorafenib with other anticancer agents for HCC have been launched with varying degrees of success. Sorafenib inhibits several kinase targets but it can also simultaneously or sequentially activate the addiction switches and compensatory pathways, inducing acquired resistance. Some other molecular targeted drugs have been used as second-line treatment for advanced HCC after the failure of sorafenib therapy. Further investigation on the crosstalk and relationship of associated pathways will better our understanding of the mechanisms accounting for sorafenib resistance in HCC.Zhai B, Sun XY. Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma. World J Hepatol 2013; 5(7): 345-352 Available from:

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“…The cell viability was measured with a Cell Counting Kit-8 (CCK-8) kit (Dojindo Molecular Technologies, Gaithersburg, MD, USA), and cell apoptosis was analyzed by flow cytometry [39,41].…”

Section: Cell Viability and Apoptosis Assaysmentioning

confidence: 99%

“…The methods for RT-PCR have been described previously [41,42]. The primers used in this study are listed in Table 1.…”

Section: Quantitative Real-time Rt-pcrmentioning

confidence: 99%

Up‐regulation of survivin by AKT and hypoxia‐inducible factor 1α contributes to cisplatin resistance in gastric cancer

et al. 2013

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This study investigated the contribution of survivin and its upstream regulators, AKT and hypoxia-inducible factor 1a , to the resistance of gastric cancer cells to cisplatin (CDDP). We found that over-expression of survivin increased the resistance of SGC7901 and BGC823 gastric cancer cells to CDDP. Its over-expression abrogated CDDP-induced inhibition of cell proliferation and CDDP-induced cell apoptosis. In contrast, down-regulation of survivin expression using small hairpin RNA (shRNA) vectors and the small-molecule inhibitor YM155, or inhibition of survivin function using a recombinant cell-permeable dominant-negative survivin protein (dNSur9), promoted CDDP-induced apoptosis. CDDP-resistant sub-lines generated from the parental SGC7901 and BGC823 cells by exposure to increasing concentrations of CDDP expressed higher levels of HIF-1a and survivin in response to hypoxia, and higher levels of phosphorylated AKT (pAKT). Specific inhibition of AKT reduced the expression of HIF-1a and survivin, whereas specific inhibition or depletion of HIF-1a reduced survivin expression but had no effect on the expression of phosphorylated AKT. The expression levels of survivin affected the therapeutic efficacy of CDDP in treating gastric tumors in mice. Specific inhibition of survivin, AKT and HIF-1a enhanced the sensitivity of CDDP-resistant cells to CDDP. Specific inhibition of survivin, AKT and HIF-1a synergized with CDDP to suppress the growth of gastric tumors that had been engineered to overexpress survivin. In summary, the results provide evidence that up-regulation of survivin by AKT and HIF-1a contributes to CDDP resistance, indicating that inhibition of these pathways may be a potential strategy for overcoming CDDP resistance in the treatment of gastric cancer.Gastric cancer is the third most frequent cause of cancer death in men worldwide [1]. Despite advances in diagnostic technology, most cases are already clinically advanced at the time of diagnosis, and hence chemotherapy is essential for treatment [2]. Cisplatin (CDDP) is the most commonly used chemotherapeutic agent for the treatment of gastric cancer [3]. The combination of CDDP and the 5-fluorouracil-related drug S-1 was established as the first-line chemotherapy for advanced gastric cancer based on a phase III trial in Abbreviations CDDP, cisplatin; dNSur9, recombinant cell-permeable dominant-negative survivin protein; HIF, hypoxia-inducible factor; 2ME2, 2-methoxyestradiol; pAKT, phosphorylated AKT; shRNA, small hairpin RNA; TCN, triciribine.

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STAT3 interacts with Skp2/p27/p21 pathway to regulate the motility and invasion of gastric cancer cells

Cited by 105 publications

References 34 publications

Inhibition of Akt Reverses the Acquired Resistance to Sorafenib by Switching Protective Autophagy to Autophagic Cell Death in Hepatocellular Carcinoma

Inhibition of Akt Reverses the Acquired Resistance to Sorafenib by Switching Protective Autophagy to Autophagic Cell Death in Hepatocellular Carcinoma

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Up‐regulation of survivin by AKT and hypoxia‐inducible factor 1α contributes to cisplatin resistance in gastric cancer

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