DJ-1 Alters Epirubicin-induced Apoptosis via Modulating Epirubicinactivated Autophagy in Human Gastric Cancer Cells

Abstract

Epirubicin, which is a conventional chemotherapeutic drug for gastric cancer, has innate and adaptive chemoresistance. Recent studies revealed that epirubicin could induce autophagy as a defensive mechanism in drug resistance of mammary carcinoma. Another study implied that DJ-1 may be a chemoresistance-related gene. But the association between DJ-1 and drug resistance of epirubicin in gastric cancer is still ambiguous. In the present report, we explored whether and how DJ-1 conduced to epirubicin-induced apoptosis in gastric cancer. Epirubicin dose-dependently increased the expression of DJ-1 and induced autophagy. Knockdown of DJ-1 notably enhanced epirubicin-induced cell apoptosis, whereas overexpression of DJ-1 attenuated epirubicin-induced cell apoptosis. Further studies revealed that down-regulation of DJ-1 modulated epirubicinactivated autophagy which augmented epirubicin-induced apoptosis. In conclusion, our results validated that DJ-1 reduced epirubicin-induced apoptosis in gastric cancer cells via modulating epirubicin-activated autophagy.

Keywords

epirubicin / gastric cancer / DJ-1 / apoptosis / autophagy

References

[1] KarimiP, IslamiF, AnandasabapathyS, et al.. Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiol Biomarkers Prev, 2014, 23(5): 700-713

[2] AnX, WangF, ShaoQ, et al.. MET amplification is not rare and predicts unfavorable clinical outcomes in patients with recurrent/metastatic gastric cancer after chemotherapy. Cancer, 2014, 120(5): 675-682

[3] TsuburayaA, MizusawaJ, TanakaY, et al.. Neoadjuvant chemotherapy with S-1 and cisplatin followed by D2 gastrectomy with para-aortic lymph node dissection for gastric cancer with extensive lymph node metastasis. Br J Surg, 2014, 101(6): 653-660

[4] NakajimaT, FujiiM. What make differences in the outcome of adjuvant treatments for resected gastric cancer. World J Gastroenterol, 2014, 20(33): 11567-11573

[5] WaddellT, ChauI, CunninghamD, et al.. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol, 2013, 14(6): 481-489

[6] SmythEC, FassanM, CunninghamD, et al.. Effect of Pathologic Tumor Response and Nodal Status on Survival in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy Trial. J Clin Oncol, 2016, 34(23): 2721-2727

[7] NagakuboD, TairaT, KitauraH, et al.. DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochem Biophys Res Commun, 1997, 231(2): 509-513

[8] MéminE, HoqueM, JainMR, et al.. Blocking eIF5A modification in cervical cancer cells alters the expression of cancer-related genes and suppresses cell proliferation. Cancer Res, 2014, 74(2): 552-562

[9] IsmailIA, KangHS, LeeHJ, et al.. DJ-1 upregulates breast cancer cell invasion by repressing KLF17 expression. Br J Cancer, 2014, 110(5): 1298-1306

[10] GaoH, NiuY, LiM, et al.. Identification of DJ-1 as a contributor to multidrug resistance in human small-cell lung cancer using proteomic analysis. Int J Exp Pathol, 2017, 98(2): 67-74

[11] LiQ, TangY, QinJ, et al.. Subcellular localization of DJ-1 in human HL-60 leukemia cells in response to diallyl disulfide treatment. Mol Med Rep, 2016, 14(5): 4666-4672

[12] ZengHZ, QuYQ, ZhangWJ, et al.. Proteomic analysis identified DJ-1 as a cisplatin resistant marker in nonsmall cell lung cancer. Int J Mol Sci, 2011, 12(6): 3489-3499

[13] ChenY, KangM, LuW, et al.. DJ-1, a novel biomarker and a selected target gene for overcoming chemoresistance in pancreatic cancer. J Cancer Res Clin Oncol, 2012, 138(9): 1463-1474

[14] LevN, BarhumY, PilosofNS, et al.. DJ-1 protects against dopamine toxicity: implications for Parkinson's disease and aging. J Gerontol A Biol Sci Med Sci, 2013, 68(3): 215-225

[15] SaraswathyM, GongS. Different strategies to overcome multidrug resistance in cancer. Biotechnol Adv, 2013, 31(8): 1397-1407

[16] YamamotoY, HyodoI, TakigahiraM, et al.. Effect of combined treatment with the epirubicin-incorporating micelles (NC-6300) and 1, 2-diaminocyclohexane platinum (II)-incorporating micelles (NC-4016) on a human gastric cancer model. Int J Cancer, 2014, 135(1): 214-223

[17] ChenW, LiuX, XiaoY, et al.. Overcoming multiple drug resistance by spatial-temporal synchronization of epirubicin and pooled siRNAs. Small, 2015, 11(15): 1775-1781

[18] CaoJ, LouS, YingM, et al.. DJ-1 as a human oncogene and potential therapeutic target. Biochem Pharmacol, 2015, 93(3): 241-250

[19] SchumannC, ChanS, KhalimonchukO, et al.. Mechanistic Nanotherapeutic Approach Based on siRNA-Mediated DJ-1 Protein Suppression for Platinum-Resistant Ovarian Cancer. Mol Pharm, 2016, 13(6): 2070-2083

[20] TrivediR, DihaziGH, EltoweissyM, et al.. The antioxidant protein PARK7 plays an important role in cell resistance to Cisplatin-induced apoptosis in case of clear cell renal cell carcinoma. Eur J Pharmacol, 2016, 784: 99-110

[21] SunWL, ChenJ, WangYP, et al.. Autophagy protects breast cancer cells from epirubicin-induced apoptosis and facilitates epirubicin-resistance development. Autophagy, 2011, 7(9): 1035-1044

[22] IsmailIA, KangHS, LeeHJ, et al.. 2'-Benzoyloxycinnamaldehyde-mediated DJ-1 upregulation protects MCF-7 cells from mitochondrial damage. Biol Pharm Bull, 2012, 35(6): 895-902