Cisplatin-mediated c-myc overexpression and cytochrome c (cyt c) release result in the up-regulation of the death receptors DR4 and DR5 and the activation of caspase 3 and caspase 9, likely responsible for the TRAIL-sensitizing effect of cisplatin

Zhu, Xingchao; Zhang, Kaiguang; Wang, Qiao-min; Chen, Si; Gou, Yawen; Cui, Yan; Li, Qin

doi:10.1007/s12032-015-0588-9

Cited by 34 publications

(25 citation statements)

References 40 publications

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“…Therefore, in the present study, it was hypothesized that overexpression of SMS2 was able to alter the expression of DR4 and DR5, and increased the expression of c-Myc, as well as increasing the sensitivity of the cells to DDP. However, DDP is also able to increase the expression of DR4 and DR5 to induce cell apoptosis (7,21). In the present study, it was demonstrated that treatment with DDP was able to significantly increase the expression of DR4 and DR5 in HepG2 cells, and the increase in the expression of DR4 and DR5 was higher in the SMS2 + DDP group compared with the control + DDP group.…”

Section: Discussionsupporting

confidence: 49%

“…Similar to TRAIL, DDP is also able to induce apoptosis through the DR4 and DR5 signaling pathways (6,7). DDP is able to trigger apoptosis through the DR4 and DR5 signal pathways in H460 cells, independent of TRAIL and the mitochondrial apoptotic pathway (9).…”

Section: Discussionmentioning

confidence: 99%

“…However, only two of the receptors, DR4 (TRAIL-R1) and DR5 (TRAIL-R2), are capable of effectively transmitting the apoptotic signal (5). A number of studies reported that DDP enhances the sensitivity of TRAIL to the cancer cells by increasing the expression of DR4 and DR5 (6,7), which triggers the relocalization of DR4 and DR5 to the cell membrane and accelerates the internalization of TRAIL (2,6,8). However, DDP can also induce apoptosis through the DR4 and DR5 signaling pathways, which is not dependent on TRAIL and the mitochondrial apoptotic signaling pathway (9).…”

Section: Introductionmentioning

confidence: 99%

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Sphingomyelin synthase 2 overexpression promotes cisplatin‑induced apoptosis of HepG2 cells

et al. 2017

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Abstract. Hepatoblastoma (HB) is the most type of common pediatric liver cancer. The primary chemotherapy drug for HB is cisplatin (DDP). However, patients readily develop intrinsic and acquired resistance, and severe side effects to treatment. Sphingomyelin synthase 2 (SMS2) is a key enzyme involved in the generation of sphingomyelin (SM), which is able to regulate cell proliferation, apoptosis and differentiation. The death receptors (DRs) have important functions in DDP-induced apoptosis. However, whether SMS2 is able to modulate cell apoptosis through the DR signaling pathway remains unknown. To investigate this question, SMS2 was overexpressed in HepG2 cells and treated with 3.5 mg/l cisplatin in the present study. After 24 h, the expression of SMS2, avian myelocytomatosis viral oncogene homolog (c-Myc), DR4, DR5 and caspase-3 was analyzed. Furthermore, cell viability was quantified, and apoptosis was assessed by western blot and flow cytometry analysis as well as Cell Counting kit-8. The results of the present study revealed that overexpression of SMS2 was able to increase the expression of c-Myc, cleaved caspase-3, DR4 and DR5 compared with the control group (P<0.05, n=3), and increase the levels of apoptosis in the SMS2 + DDP group, compared with the control (P<0.001, n=3). These results indicate that overexpression of SMS2 is able to improve sensitivity of HepG2 cells to DDP by increasing the expression of c-Myc, DR4 and DR5 in HepG2 cells. This increased sensitivity may decrease intrinsic and acquired resistance of chemotherapy in HB, and reduce the associated severe side effects in pediatric patients.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sphingomyelin synthase 2 overexpression promotes cisplatin‑induced apoptosis of HepG2 cells

et al. 2017

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“…Cytochrome-c is a mitochondrial protein. Once it is released into the cytosol, it will interact with procaspase-9, and then switch on caspase-3, leading to apoptosis [43,44]. Therefore, the authors separated the mitochondrial into crude mitochondrial and cytosolic extracts and used western blot to detect the influence of allicin on the expression of cytosolic and mitochondrial cytochrome-c.…”

Section: Discussionmentioning

confidence: 99%

Role of p38 MAPK activation and mitochondrial cytochrome-c release in allicin-induced apoptosis in SK-N-SH cells

Zhuang

Chi

2016

Anti-Cancer Drugs

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Here, we investigate the apoptotic effect of allicin, the predominant component of freshly crushed garlic, on neuroblastoma cells. In this paper, the authors have first assessed the effect of allicin on human neuroblastoma SK-N-SH cells and then investigated the underlying mechanism. The results indicate that allicin suppresses SK-N-SH cell growth in a dose-dependent and time-dependent manner and that 5 μmol/l of allicin leads to a significant increase in apoptotic rate with annexin-V/PI double staining. Western blot analysis shows that treatment with allicin-induced apoptosis through activation of caspases-3 and 9. Phosphorylation of p38 MAPK contributes to allicin-induced apoptosis upstream of caspase activation. Using p38 MAPK inhibitor, the authors discovered that p38 MAPK activation subsequently induces the release of cytochrome-c from mitochondria into the cytosol. Taken together, the results demonstrate that allicin can activate the p38 MAPK pathway, which leads to mitochondrial release of cytochrome-c, thus inducing SK-N-SH cell apoptosis. Overall, this study suggests that allicin may be used as one of the novel pharmacological treatment strategies in neuroblastoma.

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“…The Myc oncogene is another potential marker for TRAIL sensitivity in cancer cells (19)(20)(21), including those with a defective intrinsic pathway signaling route for biomarker determination (22,23). Here we demonstrate that c-Myc binds to TRAIL promoter region and is essential for its silencing in AML cells.…”

Section: Introductionmentioning

confidence: 99%

c-Myc Modulation and Acetylation Is a Key HDAC Inhibitor Target in Cancer

Nebbioso

Carafa

Conte

et al. 2017

Clinical Cancer Research

122

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Purpose: Histone deacetylase inhibitors (HDACi) are promising anticancer drugs. Although some HDACi have entered the clinic, the mechanism(s) underlying their tumor selectivity are poorly understood. Experimental Design and Results: Using gene expression analysis, we define a core set of six genes commonly regulated in acute myeloid leukemia (AML) blasts and cell lines. MYC, the most prominently modulated, is preferentially altered in leukemia. Upon HDACi treatment, c-Myc is acetylated at lysine 323 and its expression decreases, leading to TRAIL activation and apoptosis. c-Myc binds to the TRAIL promoter on the proximal GC box through SP1 or MIZ1, impairing TRAIL activation. HDACi exposure triggers TRAIL expression, altering c-Myc-TRAIL binding. These events do not occur in normal cells. Excitingly, this inverse correlation between TRAIL and c-Myc is supported by HDACi treatment ex vivo of AML blasts and primary human breast cancer cells. The predictive value of c-Myc to HDACi responsiveness is confirmed in vivo in AML patients undergoing HDACi-based clinical trials. Conclusions: Collectively, our findings identify a key role for c-Myc in TRAIL deregulation and as a biomarker of the anticancer action of HDACi in AML. The potential improved patient stratification could pave the way toward personalized therapies. Clin Cancer Res; 23(10); 2542–55. ©2016 AACR.

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Cisplatin-mediated c-myc overexpression and cytochrome c (cyt c) release result in the up-regulation of the death receptors DR4 and DR5 and the activation of caspase 3 and caspase 9, likely responsible for the TRAIL-sensitizing effect of cisplatin

Cited by 34 publications

References 40 publications

Sphingomyelin synthase 2 overexpression promotes cisplatin‑induced apoptosis of HepG2 cells

Sphingomyelin synthase 2 overexpression promotes cisplatin‑induced apoptosis of HepG2 cells

Role of p38 MAPK activation and mitochondrial cytochrome-c release in allicin-induced apoptosis in SK-N-SH cells

c-Myc Modulation and Acetylation Is a Key HDAC Inhibitor Target in Cancer

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