Study of phenethyl isothiocyanate in promoting apoptosis and proliferation of breast cancer cells through endoplasmic reticulum stress pathway_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

GUO Chenming , LI Huifang , Outikuer. Aini , LUO Zhiwen , Reyanna. Mohetaer ,  Dilimulati. Aisimutula

Department of Breast Surgery, Center of Digestive and Vascular, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, P. R. China;

Corresponding author：

Dilimulati. Aisimutula, Email: 1339280411@qq.com

Keywords：

phenethyl isothiocyanate; endoplasmic reticulum stress; breast cancer cell; apoptosis

DOI：

10.7507/1007-9424.202104103

Video：

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Objective To investigate the effects of phenethyl isothiocyanate (PEITC) on apoptosis and proliferation of breast cancer SK-BR-3 cells. Methods SK-BR-3 cells were treated with different concentrations (0, 10, 30, 50 μmol/L) of PEITC respectively. The proliferation capacity of SK-BR-3 cells was detected by MTT and BrdU staining methods. The cell apoptosis was detected by TUNEL and flow cytometry methods. The protein and mRNA expressions levels of indexes related apoptosis such as Bcl-2, Bax, and MCL-1 and indexes related endoplasmic reticulum stress (ERS) such as PERK, eIF2α, CHOP, IRE1α, ATF6α were detected by Western blot and quantitative real-time PCR (qRT-PCR), respectively. Results Compared with the control group (0 μmol/L PEITC treatment group), the results of MTT and BrdU staining methods showed that the proliferations of SK-BR-3 cells in the 10, 30 and 50 μmol/L PEITC treatment group were decreased in turn with the increase of concentration. The results of TUNEL and flow cytometry methods showed that the apoptosis rates of SK-BR-3 cells in the 10, 30 and 50 μmol/L PEITC treatment group were increased in turn with the increase of concentration. The results of Western blot and qRT-PCR methods showed that the protein and mRNA expression levels of anti-apoptotic indexes (Bcl-2, MCL-1) were decreased with the increase of concentration, while the expression levels of protein and mRNA of the pro-apoptotic index (Bax) and ERS-related indexes (PERK, eIF2α, CHOP, IRE1α, ATF6α) increased with the increase of concentration. Conclusion From the preliminary results of this study, PEITC can promote the apoptosis of breast cancer SK-BR-3 cells and inhibit cell proliferation, which might be achieved by regulating the expression levels of indexes related apoptosis and ERS.

Citation： GUO Chenming, LI Huifang, Outikuer. Aini, LUO Zhiwen, Reyanna. Mohetaer, Dilimulati. Aisimutula. Study of phenethyl isothiocyanate in promoting apoptosis and proliferation of breast cancer cells through endoplasmic reticulum stress pathway. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(1): 12-16. doi: 10.7507/1007-9424.202104103 Copy

1.	Britt KL, Cuzick J, Phillips KA. Key steps for effective breast cancer prevention. Nat Rev Cancer, 2020, 20(8): 417-436.
2.	Zhang T, Zhang W, Hao M. Phenethyl isothiocyanate reduces breast cancer stem cell-like properties by epigenetic reactivation of CDH1. Oncol Rep, 2021, 45(1): 337-348.
3.	Zhang Q, Chen M, Cao L, et al. Phenethyl isothiocyanate synergistically induces apoptosis with gefitinib in non-small cell lung cancer cells via endoplasmic reticulum stress-mediated degradation of Mcl-1. Mol Carcinog, 2020, 59(6): 590-603.
4.	Osipitan OO, Shi Y, Di Pasqua AJ. Phenethyl isothiocyanate-containing carbomer gel for use against squamous cell carcinoma. Pharmaceutics, 2021, 13(1): 106.
5.	Oakes SA. Endoplasmic reticulum stress signaling in cancer cells. Am J Pathol, 2020, 190(5): 934-946.
6.	Chen X, Cubillos-Ruiz JR. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat Rev Cancer, 2021, 21(2): 71-88.
7.	Reyes-Fermín LM, Aparicio-Trejo OE, Avila-Rojas SH, et al. Natural antioxidants’ effects on endoplasmic reticulum stress-related diseases. Food Chem Toxicol, 2020, 138: 111229.
8.	张美兰, 沈哲式, 张英哲, 等. 姜黄素诱导人肝癌 BEL-7404 细胞凋亡的内质网应激作用的研究. 吉林医学, 2021, 42(1): 5-8.
9.	林霄, 孙国平, 刘加涛. 抑制肝癌细胞内质网应激可增强槐耳清膏的抗肿瘤作用. 安徽医科大学学报, 2020, 55(12): 1822-1827.
10.	黄静莹, 陈萱, 饶靖红. 内源性大麻素 N-花生四烯酸氨基乙醇介导卵巢癌细胞自噬和内质网应激. 中国病理生理杂志, 2020, 36(11): 2020-2029.
11.	Nguyen YT, Moon JY, Ediriweera MK, et al. Phenethyl isothiocyanate suppresses stemness in the chemo- and radio-resistant triple-negative breast cancer cell line MDA-MB-231/IR via downregulation of metadherin. Cancers (Basel), 2020, 12(2): 268.
12.	Koschorke A, Faraci S, Giani D, et al. Phenethyl isothiocyanate hampers growth and progression of HER2-positive breast and ovarian carcinoma by targeting their stem cell compartment. Cell Oncol (Dordr), 2019, 42(6): 815-828.
13.	Eisa NH, Said HS, ElSherbiny NM, et al. Phenethyl isothiocyanate triggers apoptosis, combats oxidative stress and inhibits growth of ehrlich ascites carcinoma mouse model. Iran J Pharm Res, 2018, 17(4): 1328-1338.
14.	胡军, 徐丽丽, 罗毅, 等. 异硫氰酸苯乙酯经 PI3K/Akt/mTOR 途径抑制非小细胞肺癌细胞表达 c-Myc和RPS19. 中国细胞生物学学报, 2020, 42(10): 1774-1781.
15.	Hsia TC, Huang YP, Jiang YW, et al. Phenethyl isothiocyanate induces apoptotic cell death through the mitochondria-dependent pathway in gefitinib-resistant NCI-H460 human lung cancer cells in vitro. Anticancer Res, 2018, 38(4): 2137-2147.
16.	Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol, 2020, 21(8): 421-438.
17.	Dilly AK, Honick BD, Lee YJ, et al. Synergistic apoptosis following endoplasmic reticulum stress aggravation in mucinous colon cancer. Orphanet J Rare Dis, 2020, 15(1): 211.
18.	Park WJ, Park JW. The role of sphingolipids in endoplasmic reticulum stress. FEBS Lett, 2020, 594(22): 3632-3651.
19.	Park SJ, Li C, Chen YM. Endoplasmic reticulum calcium homeostasis in kidney disease: pathogenesis and therapeutic targets. Am J Pathol, 2021, 191(2): 256-265.
20.	Cakir I, Nillni EA. Endoplasmic reticulum stress, the hypothalamus, and energy balance. Trends Endocrinol Metab, 2019, 30(3): 163-176.

1. Britt KL, Cuzick J, Phillips KA. Key steps for effective breast cancer prevention. Nat Rev Cancer, 2020, 20(8): 417-436.
2. Zhang T, Zhang W, Hao M. Phenethyl isothiocyanate reduces breast cancer stem cell-like properties by epigenetic reactivation of CDH1. Oncol Rep, 2021, 45(1): 337-348.
3. Zhang Q, Chen M, Cao L, et al. Phenethyl isothiocyanate synergistically induces apoptosis with gefitinib in non-small cell lung cancer cells via endoplasmic reticulum stress-mediated degradation of Mcl-1. Mol Carcinog, 2020, 59(6): 590-603.
4. Osipitan OO, Shi Y, Di Pasqua AJ. Phenethyl isothiocyanate-containing carbomer gel for use against squamous cell carcinoma. Pharmaceutics, 2021, 13(1): 106.
5. Oakes SA. Endoplasmic reticulum stress signaling in cancer cells. Am J Pathol, 2020, 190(5): 934-946.
6. Chen X, Cubillos-Ruiz JR. Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat Rev Cancer, 2021, 21(2): 71-88.
7. Reyes-Fermín LM, Aparicio-Trejo OE, Avila-Rojas SH, et al. Natural antioxidants’ effects on endoplasmic reticulum stress-related diseases. Food Chem Toxicol, 2020, 138: 111229.
8. 张美兰, 沈哲式, 张英哲, 等. 姜黄素诱导人肝癌 BEL-7404 细胞凋亡的内质网应激作用的研究. 吉林医学, 2021, 42(1): 5-8.
9. 林霄, 孙国平, 刘加涛. 抑制肝癌细胞内质网应激可增强槐耳清膏的抗肿瘤作用. 安徽医科大学学报, 2020, 55(12): 1822-1827.
10. 黄静莹, 陈萱, 饶靖红. 内源性大麻素 N-花生四烯酸氨基乙醇介导卵巢癌细胞自噬和内质网应激. 中国病理生理杂志, 2020, 36(11): 2020-2029.
11. Nguyen YT, Moon JY, Ediriweera MK, et al. Phenethyl isothiocyanate suppresses stemness in the chemo- and radio-resistant triple-negative breast cancer cell line MDA-MB-231/IR via downregulation of metadherin. Cancers (Basel), 2020, 12(2): 268.
12. Koschorke A, Faraci S, Giani D, et al. Phenethyl isothiocyanate hampers growth and progression of HER2-positive breast and ovarian carcinoma by targeting their stem cell compartment. Cell Oncol (Dordr), 2019, 42(6): 815-828.
13. Eisa NH, Said HS, ElSherbiny NM, et al. Phenethyl isothiocyanate triggers apoptosis, combats oxidative stress and inhibits growth of ehrlich ascites carcinoma mouse model. Iran J Pharm Res, 2018, 17(4): 1328-1338.
14. 胡军, 徐丽丽, 罗毅, 等. 异硫氰酸苯乙酯经 PI3K/Akt/mTOR 途径抑制非小细胞肺癌细胞表达 c-Myc和RPS19. 中国细胞生物学学报, 2020, 42(10): 1774-1781.
15. Hsia TC, Huang YP, Jiang YW, et al. Phenethyl isothiocyanate induces apoptotic cell death through the mitochondria-dependent pathway in gefitinib-resistant NCI-H460 human lung cancer cells in vitro. Anticancer Res, 2018, 38(4): 2137-2147.
16. Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol, 2020, 21(8): 421-438.
17. Dilly AK, Honick BD, Lee YJ, et al. Synergistic apoptosis following endoplasmic reticulum stress aggravation in mucinous colon cancer. Orphanet J Rare Dis, 2020, 15(1): 211.
18. Park WJ, Park JW. The role of sphingolipids in endoplasmic reticulum stress. FEBS Lett, 2020, 594(22): 3632-3651.
19. Park SJ, Li C, Chen YM. Endoplasmic reticulum calcium homeostasis in kidney disease: pathogenesis and therapeutic targets. Am J Pathol, 2021, 191(2): 256-265.
20. Cakir I, Nillni EA. Endoplasmic reticulum stress, the hypothalamus, and energy balance. Trends Endocrinol Metab, 2019, 30(3): 163-176.

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Study of phenethyl isothiocyanate in promoting apoptosis and proliferation of breast cancer cells through endoplasmic reticulum stress pathway

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