Skip to main content
Top
Published in: BMC Complementary Medicine and Therapies 1/2023

Open Access 01-12-2023 | Neuroblastoma | Research

Prevention of STAT3-related pathway in SK-N-SH cells by natural product astaxanthin

Authors: Shao-Qian Sun, Feng-Xiang Du, Li-Hua Zhang, Hao-Shi, Fu-Ying Gu, Yu-Lin Deng, Yi-Zhi Ji

Published in: BMC Complementary Medicine and Therapies | Issue 1/2023

Login to get access

Abstract

Purpose

Neuroblastoma (NB) is the most common solid malignancy in children. Despite current intensive treatment, the long-term event-free survival rate is less than 50% in these patients. Thus, patients with NB urgently need more valid treatment strategies. Previous research has shown that STAT3 may be an effective target in high-risk NB patients. However, there are no effective inhibitors in clinical evaluation with low toxicity and few side effects. Astaxanthin is a safe and natural anticancer product. In this study, we investigated whether astaxanthin could exert antitumor effects in the SK-N-SH neuroblastoma cancer cell line.

Method

MTT and colony formation assays were used to determine the effect of astaxanthin on the proliferation and colony formation of SK-N-SH cells. Flow cytometry assays were used to detect the apoptosis of SK-N-SH cells. The migration and invasion ability of SK-N-SH cells were detected by migration and invasion assays. Western blot and RT-PCR were used to detect the protein and mRNA levels. Animal experiments were carried out and cell apoptosis in tissues were assessed using a TUNEL assay.

Result

We confirmed that astaxanthin repressed proliferation, clone formation ability, migration and invasion and induced apoptosis in SK-N-SH cells through the STAT3 pathway. Furthermore, the highest inhibitory effect was observed when astaxanthin was combined with si-STAT3. The reason for this may be that the combination of astaxanthin and si-STAT3 can lower STAT3 expression further than astaxanthin or si-STAT3 alone.

Conclusion

Astaxanthin can exert anti-tumor effect on SK-N-SH cells. The inhibitory effect was the higher when astaxanthin was combined with si-STAT3.
Appendix
Available only for authorised users
Literature
3.
go back to reference Orr KE, McHugh K. The new international neuroblastoma response criteria. Pediatr Radiol. 2019;49(11):1433–40.CrossRefPubMed Orr KE, McHugh K. The new international neuroblastoma response criteria. Pediatr Radiol. 2019;49(11):1433–40.CrossRefPubMed
4.
go back to reference Gutierrez JC, et al. Markedly improving survival of neuroblastoma: a 30-year analysis of 1,646 patients. Pediatr Surg Int. 2007;23(7):637–46.CrossRefPubMed Gutierrez JC, et al. Markedly improving survival of neuroblastoma: a 30-year analysis of 1,646 patients. Pediatr Surg Int. 2007;23(7):637–46.CrossRefPubMed
6.
7.
go back to reference Wang HQ et al. STAT3 pathway in cancers: Past, present, and future MedComm (2020), 2022. 3(2): p. e124. Wang HQ et al. STAT3 pathway in cancers: Past, present, and future MedComm (2020), 2022. 3(2): p. e124.
8.
go back to reference Al Zaid Siddiquee K, Turkson J. STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res. 2008;18(2):254–67.CrossRefPubMed Al Zaid Siddiquee K, Turkson J. STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res. 2008;18(2):254–67.CrossRefPubMed
9.
go back to reference Zhang J, et al. Upregulation of the signal transducers and activators of transcription 3 (STAT3) pathway in lymphatic metastases of papillary thyroid cancer. Int J Clin Exp Pathol. 2011;4(4):356–62.PubMedPubMedCentral Zhang J, et al. Upregulation of the signal transducers and activators of transcription 3 (STAT3) pathway in lymphatic metastases of papillary thyroid cancer. Int J Clin Exp Pathol. 2011;4(4):356–62.PubMedPubMedCentral
10.
go back to reference Jiang Y, et al. Inflammatory microenvironment of fibrotic liver promotes hepatocellular carcinoma growth, Metastasis and sorafenib resistance through STAT3 activation. J Cell Mol Med. 2021;25(3):1568–82.CrossRefPubMedPubMedCentral Jiang Y, et al. Inflammatory microenvironment of fibrotic liver promotes hepatocellular carcinoma growth, Metastasis and sorafenib resistance through STAT3 activation. J Cell Mol Med. 2021;25(3):1568–82.CrossRefPubMedPubMedCentral
11.
go back to reference Eroglu M, et al. STAT3 expression is correlated with pathological stage in luminal subtypes of breast carcinoma. Bratisl Lek Listy. 2020;121(1):51–61.PubMed Eroglu M, et al. STAT3 expression is correlated with pathological stage in luminal subtypes of breast carcinoma. Bratisl Lek Listy. 2020;121(1):51–61.PubMed
13.
go back to reference Cirmi S, et al. Oleacein inhibits STAT3, activates the apoptotic machinery, and exerts anti-metastatic effects in the SH-SY5Y human neuroblastoma cells. Food Funct. 2020;11(4):3271–9.CrossRefPubMed Cirmi S, et al. Oleacein inhibits STAT3, activates the apoptotic machinery, and exerts anti-metastatic effects in the SH-SY5Y human neuroblastoma cells. Food Funct. 2020;11(4):3271–9.CrossRefPubMed
14.
15.
go back to reference Odate S, et al. Inhibition of STAT3 with the Generation 2.5 antisense oligonucleotide, AZD9150, decreases Neuroblastoma Tumorigenicity and increases Chemosensitivity. Clin Cancer Res. 2017;23(7):1771–84.CrossRefPubMed Odate S, et al. Inhibition of STAT3 with the Generation 2.5 antisense oligonucleotide, AZD9150, decreases Neuroblastoma Tumorigenicity and increases Chemosensitivity. Clin Cancer Res. 2017;23(7):1771–84.CrossRefPubMed
16.
go back to reference Hadjidaniel MD, et al. Tumor-associated macrophages promote neuroblastoma via STAT3 phosphorylation and up-regulation of c-MYC. Oncotarget. 2017;8(53):91516–29.CrossRefPubMedPubMedCentral Hadjidaniel MD, et al. Tumor-associated macrophages promote neuroblastoma via STAT3 phosphorylation and up-regulation of c-MYC. Oncotarget. 2017;8(53):91516–29.CrossRefPubMedPubMedCentral
17.
go back to reference Agarwal S, et al. G-CSF promotes Neuroblastoma Tumorigenicity and Metastasis via STAT3-Dependent Cancer stem cell activation. Cancer Res. 2015;75(12):2566–79.CrossRefPubMedPubMedCentral Agarwal S, et al. G-CSF promotes Neuroblastoma Tumorigenicity and Metastasis via STAT3-Dependent Cancer stem cell activation. Cancer Res. 2015;75(12):2566–79.CrossRefPubMedPubMedCentral
18.
go back to reference Wang XH, et al. IGF1R facilitates epithelial-mesenchymal transition and cancer stem cell properties in neuroblastoma via the STAT3/AKT axis. Cancer Manag Res. 2019;11:5459–72.CrossRefPubMedPubMedCentral Wang XH, et al. IGF1R facilitates epithelial-mesenchymal transition and cancer stem cell properties in neuroblastoma via the STAT3/AKT axis. Cancer Manag Res. 2019;11:5459–72.CrossRefPubMedPubMedCentral
19.
go back to reference Okusaka T, et al. Phase 1 and pharmacological trial of OPB-31121, a signal transducer and activator of transcription-3 inhibitor, in patients with advanced hepatocellular carcinoma. Hepatol Res. 2015;45(13):1283–91.CrossRefPubMed Okusaka T, et al. Phase 1 and pharmacological trial of OPB-31121, a signal transducer and activator of transcription-3 inhibitor, in patients with advanced hepatocellular carcinoma. Hepatol Res. 2015;45(13):1283–91.CrossRefPubMed
21.
go back to reference Lin L, et al. A small molecule, LLL12 inhibits constitutive STAT3 and IL-6-induced STAT3 signaling and exhibits potent growth suppressive activity in human Multiple Myeloma cells. Int J Cancer. 2012;130(6):1459–69.CrossRefPubMed Lin L, et al. A small molecule, LLL12 inhibits constitutive STAT3 and IL-6-induced STAT3 signaling and exhibits potent growth suppressive activity in human Multiple Myeloma cells. Int J Cancer. 2012;130(6):1459–69.CrossRefPubMed
22.
go back to reference Ko HJ, Kim YJ. Signal transducer and activator of transcription proteins: regulators of myeloid-derived suppressor cell-mediated immunosuppression in cancer. Arch Pharm Res. 2016;39(11):1597–608.CrossRefPubMed Ko HJ, Kim YJ. Signal transducer and activator of transcription proteins: regulators of myeloid-derived suppressor cell-mediated immunosuppression in cancer. Arch Pharm Res. 2016;39(11):1597–608.CrossRefPubMed
23.
go back to reference Efsa Panel on Nutrition, N.F. Safety of astaxanthin for its use as a novel food in food supplements. EFSA J. 2020;18(2):e05993. Efsa Panel on Nutrition, N.F. Safety of astaxanthin for its use as a novel food in food supplements. EFSA J. 2020;18(2):e05993.
24.
go back to reference Miki W, Yamaguchi K, Konosu S. Comparison of carotenoids in the ovaries of marine fish and Shellfish. Comp Biochem Physiol B. 1982;71(1):7–11.CrossRefPubMed Miki W, Yamaguchi K, Konosu S. Comparison of carotenoids in the ovaries of marine fish and Shellfish. Comp Biochem Physiol B. 1982;71(1):7–11.CrossRefPubMed
25.
go back to reference Guerin M, Huntley ME, Olaizola M. Haematococcus astaxanthin: applications for human health and nutrition. Trends Biotechnol. 2003;21(5):210–6.CrossRefPubMed Guerin M, Huntley ME, Olaizola M. Haematococcus astaxanthin: applications for human health and nutrition. Trends Biotechnol. 2003;21(5):210–6.CrossRefPubMed
26.
go back to reference Lee J, Kim MH, Kim H. Anti-oxidant and anti-inflammatory effects of Astaxanthin on Gastrointestinal Diseases. Int J Mol Sci, 2022. 23(24). Lee J, Kim MH, Kim H. Anti-oxidant and anti-inflammatory effects of Astaxanthin on Gastrointestinal Diseases. Int J Mol Sci, 2022. 23(24).
27.
go back to reference Si P, Zhu C. Biological and neurological activities of astaxanthin (review). Mol Med Rep, 2022. 26(4). Si P, Zhu C. Biological and neurological activities of astaxanthin (review). Mol Med Rep, 2022. 26(4).
28.
go back to reference Song XD, et al. Astaxanthin induces mitochondria-mediated apoptosis in rat hepatocellular carcinoma CBRH-7919 cells. Biol Pharm Bull. 2011;34(6):839–44.CrossRefPubMed Song XD, et al. Astaxanthin induces mitochondria-mediated apoptosis in rat hepatocellular carcinoma CBRH-7919 cells. Biol Pharm Bull. 2011;34(6):839–44.CrossRefPubMed
29.
go back to reference Zhou Q, et al. A positive Feedback Loop of AKR1C3-Mediated activation of NF-kappaB and STAT3 facilitates proliferation and Metastasis in Hepatocellular Carcinoma. Cancer Res. 2021;81(5):1361–74.CrossRefPubMed Zhou Q, et al. A positive Feedback Loop of AKR1C3-Mediated activation of NF-kappaB and STAT3 facilitates proliferation and Metastasis in Hepatocellular Carcinoma. Cancer Res. 2021;81(5):1361–74.CrossRefPubMed
30.
go back to reference Jin W. Role of JAK/STAT3 signaling in the regulation of Metastasis, the transition of Cancer Stem cells, and Chemoresistance of Cancer by epithelial-mesenchymal transition. Cells, 2020. 9(1). Jin W. Role of JAK/STAT3 signaling in the regulation of Metastasis, the transition of Cancer Stem cells, and Chemoresistance of Cancer by epithelial-mesenchymal transition. Cells, 2020. 9(1).
31.
go back to reference Song J, et al. Discovery of STAT3 inhibitors: recent advances and future perspectives. Curr Med Chem. 2023;30(16):1824–47.CrossRefPubMed Song J, et al. Discovery of STAT3 inhibitors: recent advances and future perspectives. Curr Med Chem. 2023;30(16):1824–47.CrossRefPubMed
32.
go back to reference Huang Q, et al. Revisiting signal transducer and activator of transcription 3 (STAT3) as an anticancer target and its inhibitor discovery: where are we and where should we go? Eur J Med Chem. 2020;187:111922.CrossRefPubMed Huang Q, et al. Revisiting signal transducer and activator of transcription 3 (STAT3) as an anticancer target and its inhibitor discovery: where are we and where should we go? Eur J Med Chem. 2020;187:111922.CrossRefPubMed
33.
go back to reference Hong D, et al. AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in Lymphoma and Lung cancer. Sci Transl Med. 2015;7(314):314ra185.CrossRefPubMedPubMedCentral Hong D, et al. AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in Lymphoma and Lung cancer. Sci Transl Med. 2015;7(314):314ra185.CrossRefPubMedPubMedCentral
34.
go back to reference Modak S, Cheung NK. Neuroblastoma: therapeutic strategies for a clinical enigma. Cancer Treat Rev. 2010;36(4):307–17.CrossRefPubMed Modak S, Cheung NK. Neuroblastoma: therapeutic strategies for a clinical enigma. Cancer Treat Rev. 2010;36(4):307–17.CrossRefPubMed
35.
go back to reference Liu WH, et al. Cisplatin-selected resistance is associated with increased motility and stem-like properties via activation of STAT3/Snail axis in atypical teratoid/rhabdoid Tumor cells. Oncotarget. 2015;6(3):1750–68.CrossRefPubMedPubMedCentral Liu WH, et al. Cisplatin-selected resistance is associated with increased motility and stem-like properties via activation of STAT3/Snail axis in atypical teratoid/rhabdoid Tumor cells. Oncotarget. 2015;6(3):1750–68.CrossRefPubMedPubMedCentral
36.
go back to reference Chen RJ, et al. Long-term nicotine exposure-induced chemoresistance is mediated by activation of Stat3 and downregulation of ERK1/2 via nAChR and beta-adrenoceptors in human Bladder cancer cells. Toxicol Sci. 2010;115(1):118–30.CrossRefPubMed Chen RJ, et al. Long-term nicotine exposure-induced chemoresistance is mediated by activation of Stat3 and downregulation of ERK1/2 via nAChR and beta-adrenoceptors in human Bladder cancer cells. Toxicol Sci. 2010;115(1):118–30.CrossRefPubMed
37.
go back to reference Alas S, Bonavida B. Inhibition of constitutive STAT3 activity sensitizes resistant non-hodgkin’s Lymphoma and Multiple Myeloma to chemotherapeutic drug-mediated apoptosis. Clin Cancer Res. 2003;9(1):316–26.PubMed Alas S, Bonavida B. Inhibition of constitutive STAT3 activity sensitizes resistant non-hodgkin’s Lymphoma and Multiple Myeloma to chemotherapeutic drug-mediated apoptosis. Clin Cancer Res. 2003;9(1):316–26.PubMed
38.
go back to reference Wang Y, et al. Inhibition of STAT3 reverses alkylator resistance through modulation of the AKT and beta-catenin signaling pathways. Oncol Rep. 2011;26(5):1173–80.PubMed Wang Y, et al. Inhibition of STAT3 reverses alkylator resistance through modulation of the AKT and beta-catenin signaling pathways. Oncol Rep. 2011;26(5):1173–80.PubMed
39.
go back to reference Duan Z, et al. Signal transducers and activators of transcription 3 pathway activation in drug-resistant Ovarian cancer. Clin Cancer Res. 2006;12(17):5055–63.CrossRefPubMed Duan Z, et al. Signal transducers and activators of transcription 3 pathway activation in drug-resistant Ovarian cancer. Clin Cancer Res. 2006;12(17):5055–63.CrossRefPubMed
40.
go back to reference Ishii Y, Waxman S, Germain D. Tamoxifen stimulates the growth of cyclin D1-overexpressing Breast cancer cells by promoting the activation of signal transducer and activator of transcription 3. Cancer Res. 2008;68(3):852–60.CrossRefPubMed Ishii Y, Waxman S, Germain D. Tamoxifen stimulates the growth of cyclin D1-overexpressing Breast cancer cells by promoting the activation of signal transducer and activator of transcription 3. Cancer Res. 2008;68(3):852–60.CrossRefPubMed
41.
go back to reference Redell MS, et al. Stat3 signaling in acute Myeloid Leukemia: ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor. Blood. 2011;117(21):5701–9.CrossRefPubMedPubMedCentral Redell MS, et al. Stat3 signaling in acute Myeloid Leukemia: ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor. Blood. 2011;117(21):5701–9.CrossRefPubMedPubMedCentral
42.
go back to reference Duan Z, et al. CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant Ovarian cancer cells. Cancer Chemother Pharmacol. 2009;63(4):681–9.CrossRefPubMed Duan Z, et al. CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant Ovarian cancer cells. Cancer Chemother Pharmacol. 2009;63(4):681–9.CrossRefPubMed
43.
go back to reference Yang Z, et al. Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop. Oncotarget. 2015;6(7):5072–87.CrossRefPubMed Yang Z, et al. Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop. Oncotarget. 2015;6(7):5072–87.CrossRefPubMed
44.
45.
go back to reference Davinelli S, Nielsen ME, Scapagnini G. Astaxanthin in skin health, repair, and Disease: a Comprehensive Review. Nutrients, 2018. 10(4). Davinelli S, Nielsen ME, Scapagnini G. Astaxanthin in skin health, repair, and Disease: a Comprehensive Review. Nutrients, 2018. 10(4).
Metadata
Title
Prevention of STAT3-related pathway in SK-N-SH cells by natural product astaxanthin
Authors
Shao-Qian Sun
Feng-Xiang Du
Li-Hua Zhang
Hao-Shi
Fu-Ying Gu
Yu-Lin Deng
Yi-Zhi Ji
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2023
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-023-04267-3

Other articles of this Issue 1/2023

BMC Complementary Medicine and Therapies 1/2023 Go to the issue