Enhanced Stim1 expression is associated with acquired chemo-resistance of cisplatin in osteosarcoma cells

Sun, Xiaogang; Wei, Qiang; Cheng, Jie; Bian, Yanzhu; Tian, Congna; Hu, Yujing; Li, Huijie

doi:10.1007/s13577-017-0167-9

Cited by 27 publications

(20 citation statements)

References 29 publications

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“…To accomplish this, both the parental and the CisR OC cells were treated with 50 µM of cisplatin for 24 h. Our results revealed that CisR cells had a poor apoptotic signature profile with a reduced level of apoptotic proteins (Bax, cleaved caspase-9 and cleaved caspase-3) and an increased level of anti-apoptotic protein (Bcl-2) compared to parental OC cells ( Figure 5 C,D) [ 50 ]. Subsequently, cisplatin significantly increased the expression of molecular markers of ER stress, such as GRP78, CHOP in parental OC cells compared to CisR OC cells [ 51 , 52 ]. Taken together, these findings demonstrate that cisplatin-induced ER stress-mediated apoptosis was significantly diminished in the CisR cells compared to the parental OC cells, which may point to an important underlying mechanism of CisR OC to avoid cellular death by cisplatin.…”

Section: Resultsmentioning

confidence: 99%

Establishment of Acquired Cisplatin Resistance in Ovarian Cancer Cell Lines Characterized by Enriched Metastatic Properties with Increased Twist Expression

Bahar

Kim

et al. 2020

IJMS

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Ovarian cancer (OC) is the most lethal of the gynecologic cancers, and platinum-based treatment is a part of the standard first-line chemotherapy regimen. However, rapid development of acquired cisplatin resistance remains the main cause of treatment failure, and the underlying mechanism of resistance in OC treatment remains poorly understood. Faced with this problem, our aim in this study was to generate cisplatin-resistant (CisR) OC cell models in vitro and investigate the role of epithelial–mesenchymal transition (EMT) transcription factor Twist on acquired cisplatin resistance in OC cell models. To achieve this aim, OC cell lines OV-90 and SKOV-3 were exposed to cisplatin using pulse dosing and stepwise dose escalation methods for a duration of eight months, and a total of four CisR sublines were generated, two for each cell line. The acquired cisplatin resistance was confirmed by determination of 50% inhibitory concentration (IC50) and clonogenic survival assay. Furthermore, the CisR cells were studied to assess their respective characteristics of metastasis, EMT phenotype, DNA repair and endoplasmic reticulum stress-mediated cell death. We found the IC50 of CisR cells to cisplatin was 3–5 times higher than parental cells. The expression of Twist and metastatic ability of CisR cells were significantly greater than those of sensitive cells. The CisR cells displayed an EMT phenotype with decreased epithelial cell marker E-cadherin and increased mesenchymal proteins N-cadherin and vimentin. We observed that CisR cells showed significantly higher expression of DNA repair proteins, X-ray repair cross-complementing protein 1 (XRCC1) and poly (ADP-ribose) polymerases 1 (PARP1), with significantly reduced endoplasmic reticulum (ER) stress-mediated cell death. Moreover, Twist knockdown reduced metastatic ability of CisR cells by suppressing EMT, DNA repair and inducing ER stress-induced cell death. In conclusion, we highlighted the utilization of an acquired cisplatin resistance model to identify the potential role of Twist as a therapeutic target to reverse acquired cisplatin resistance in OC.

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Section: Resultsmentioning

confidence: 99%

Establishment of Acquired Cisplatin Resistance in Ovarian Cancer Cell Lines Characterized by Enriched Metastatic Properties with Increased Twist Expression

Bahar

Kim

et al. 2020

IJMS

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“…OS has high morbidity and mortality. Moreover, the use of chemotherapy (cisplatin; Chen, 2017 ; Sun et al, 2017 ), doxorubicin (Hattinger et al, 2017 ; Zhang et al, 2017 ), and methotrexate (Valle et al, 2016 ; Ray et al, 2017 ) results in marginal improvement in survival rate even after surgery. The most serious problem is that survival rates have changed little over the past decades because no new drug is available.…”

Section: Introductionmentioning

confidence: 99%

Alginate Oligosaccharide DP5 Exhibits Antitumor Effects in Osteosarcoma Patients following Surgery

Chen

Zhang

et al. 2017

Front. Pharmacol.

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Osteosarcoma is a malignant musculoskeletal tumor that has high-rate morbidity and mortality worldwide. Alginate oligosaccharide (AOS), a natural product, has antitumor activities and may have therapeutic effects in osteosarcoma, the molecular mechanisms of which remain unclear. AOS was prepared from alginate sodium using alginate lyase. The fractions of AOS were further isolated by size-exclusion chromatography and verified by electrospray ionization mass spectrometry (ESI-MS). Osteosarcoma patients were enrolled in the study and assigned into two groups: AOS (AG, oral administration of 10-mg AOS daily) and control groups (CG, placebo). Preoperative and postoperative clinical data were investigated and analyzed. Four different degrees of polymerizations (DPs) were isolated and denominated as DP2, DP3, DP4, and DP5. Among these polymers, only DP5 showed antitumor functions on osteosarcoma cells. Before surgery and the outcome of primary end point after surgery, no significant differences were observed for clinical data and tumor size between the AG and CG groups (P > 0.05). After 2-year therapy, the mean tumor volume was 214.6 ± 145.7 c.c. in AG and 467.2 ± 225.3 c.c in CG (P < 0.01). The rate of local recurrence was 44.9 and 68.7% in AG and CG, respectively (P < 0.01). AOS treatment resulted in the increase in serum levels of SOD, GSH, HDL-C, and reduction in the levels of interleukin-1 (IL-1) beta and IL-6; the ratios of AST/ALT; and triglycerides, total cholesterol (TC), low-density lipoprotein cholesterol LDL-C, and malondialdehyde (MDA) (P < 0.05). AOS reduces osteosarcoma progression, which is associated with improvement in antioxidant and anti-inflammatory capacities of patients, and may be used as a potential drug for osteosarcoma therapy.

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“…Osteosarcoma is the most common, malignant primary bone tumor in children and adolescents ( Kansara et al, 2014 ; Valery et al, 2015 ; Gianferante et al, 2017 ). Over the last 20 years, cisplatin has been commonly used as an anticancer drug to treat osteosarcoma ( Jaffe, 2014 ; Isakoff et al, 2015 ; Sun et al, 2017 ). However, there has been no improvement in the survival of patients with drug-resistant osteosarcoma ( Lin et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

TIMP3 Overexpression Improves the Sensitivity of Osteosarcoma to Cisplatin by Reducing IL-6 Production

Han

Liu

et al. 2018

Front. Genet.

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Osteosarcoma is the most common bone cancer in children and adolescents. Tissue inhibitors of metalloproteinases (TIMPs)-3 inhibit matrix metalloproteinases to limit extracellular matrix degradation. Cisplatin is a widely used chemotherapeutic drug used to cure osteosarcoma. Interleukin (IL)-6 and TIMP3 play important roles in the drug resistance of osteosarcoma; however, their relationship in this process remains unclear. This study aimed to explore the role of TIMP3 in the cisplatin sensitivity of osteosarcoma and its underlying molecular mechanisms in vitro and in vivo. We compared TIMP3 expression levels between patients with cisplatin-sensitive and -insensitive osteosarcoma. TIMP3 was overexpressed or knocked down in the Saos2-lung cell line, which is a Saos2 subtype isolated from pulmonary metastases that has higher cisplatin chemoresistance than Saos2 cells. IL-6 expression, cell proliferation, sensitivity to cisplatin, migration, and invasion after TIMP3 overexpression or knockdown were determined. The same experiments were performed using MG63 and U2OS cells. Subsequently, luciferase-labeled Saos2-lung cells overexpressing TIMP3 were injected into the tibiae of nude mice treated with cisplatin. The results showed that IL-6 inhibited TIMP3 expression in Saos2 and Saos2-lung cells via signal transducer and activator of transcription 3 (STAT3) activation. STAT3 knockdown reversed the effect of IL-6. The expression of TIMP3 was higher in patients with cisplatin-sensitive osteosarcoma than in those with insensitive osteosarcoma. IL-6 expression was downregulated upon TIMP3 overexpression, and upregulated by TIMP3 knockdown. TIMP3 overexpression suppressed cell proliferation and enhanced cisplatin sensitivity by activating apoptosis-related signal pathways and inhibiting IL-6 expression in vitro and in vivo. In conclusion, cisplatin sensitivity correlated positively with TIMP3 expression, which is regulated by the IL-6/TIMP3/caspase pathway. The TIMP3 pathway could represent a target for new therapies to treat osteosarcoma.

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Enhanced Stim1 expression is associated with acquired chemo-resistance of cisplatin in osteosarcoma cells

Cited by 27 publications

References 29 publications

Establishment of Acquired Cisplatin Resistance in Ovarian Cancer Cell Lines Characterized by Enriched Metastatic Properties with Increased Twist Expression

Establishment of Acquired Cisplatin Resistance in Ovarian Cancer Cell Lines Characterized by Enriched Metastatic Properties with Increased Twist Expression

Alginate Oligosaccharide DP5 Exhibits Antitumor Effects in Osteosarcoma Patients following Surgery

TIMP3 Overexpression Improves the Sensitivity of Osteosarcoma to Cisplatin by Reducing IL-6 Production

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