GPX3 represses pancreatic cancer cell proliferation, migration and invasion, and improves their chemo‑sensitivity by regulating the JNK/c‑Jun signaling pathway

Ma,Ye; Zhang,Lixing; Gao,Xin; Zhu,Dongming

doi:10.3892/etm.2024.12407

GPX3 represses pancreatic cancer cell proliferation, migration and invasion, and improves their chemo‑sensitivity by regulating the JNK/c‑Jun signaling pathway

Authors:
- Ye Ma
- Lixing Zhang
- Xin Gao
- Dongming Zhu
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Affiliations: Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China, Medical Laboratory, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu 215163, P.R. China
Published online on: January 29, 2024 https://doi.org/10.3892/etm.2024.12407
Article Number: 118
Copyright: © Ma et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pancreatic cancer (PC) is a deadly and aggressive disease, which is characterized by poor prognosis. It has been reported that glutathione peroxidase 3 (GPX3) is involved in the development of several types of cancer. The present study aimed to explore the regulatory role of GPX3 in PC and uncover its underlying mechanism. Bioinformatics analysis was initially carried out to predict the expression profile of GPX3 in PC and its association with prognosis. The expression levels of GPX3 were also detected in PC cells by reverse transcription‑quantitative PCR and western blot analysis. Following transfection to induce GPX3 overexpression, the proliferation ability of PC cells was assessed by Cell Counting Kit‑8, colony formation and 5‑ethynyl‑2'‑deoxyuridine incorporation assays. In addition, wound healing and Transwell assays were performed to evaluate the migration and invasion abilities of PC cells. Cell apoptosis was assessed by flow cytometric analysis. The expression levels of epithelial‑mesenchymal transition (EMT)‑, apoptosis‑, and JNK signaling‑related proteins were detected by western blot analysis. Additionally, for rescue experiments, JNK signaling was activated following cell treatment with anisomycin. The results showed that GPX3 was downregulated in PC and its expression was associated with favorable prognosis. In addition, cell transfection‑induced GPX3 overexpression markedly inhibited cell proliferation, migration and invasion, and inhibited EMT. In addition, GPX3 improved the chemo‑sensitivity of PC and gemcitabine (GEM)‑resistant PC cells to GEM. Furthermore, GPX3 significantly suppressed JNK/c‑Jun signaling in PC, while anisomycin treatment reversed the inhibitory effects of GPX3 on the malignant behavior and chemo‑resistance of PC cells. The results of the present study indicated that GPX3 could serve as a tumor suppressor in PC via inhibiting JNK/c‑Jun signaling, thus providing novel insights into the treatment of PC.

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1	Lippi G and Mattiuzzi C: The global burden of pancreatic cancer. Arch Med Sci. 16:820–824. 2020.PubMed/NCBI View Article : Google Scholar
2	Bengtsson A, Andersson R and Ansari D: The actual 5-year survivors of pancreatic ductal adenocarcinoma based on real-world data. Sci Rep. 10(16425)2020.PubMed/NCBI View Article : Google Scholar
3	Doleh Y, Lal LS, Blauer-Petersen C, Antico G and Pishvaian M: Treatment patterns and outcomes in pancreatic cancer: Retrospective claims analysis. Cancer Med. 9:3463–3476. 2020.PubMed/NCBI View Article : Google Scholar
4	Kolbeinsson HM, Chandana S, Wright GP and Chung M: Pancreatic cancer: A review of current treatment and novel therapies. J Invest Surg. 36(2129884)2023.PubMed/NCBI View Article : Google Scholar
5	Dauer P, Nomura A, Saluja A and Banerjee S: Microenvironment in determining chemo-resistance in pancreatic cancer: Neighborhood matters. Pancreatology. 17:7–12. 2017.PubMed/NCBI View Article : Google Scholar
6	Yang Z, Wang S, Yin K, Zhang Q and Li S: MiR-1696/GPx3 axis is involved in oxidative stress mediated neutrophil extracellular traps inhibition in chicken neutrophils. J Cell Physiol. 236:3688–3699. 2021.PubMed/NCBI View Article : Google Scholar
7	Takahashi K, Avissar N, Whitin J and Cohen H: Purification and characterization of human plasma glutathione peroxidase: A selenoglycoprotein distinct from the known cellular enzyme. Arch Biochem Biophys. 256:677–686. 1987.PubMed/NCBI View Article : Google Scholar
8	Chang C, Worley BL, Phaeton R and Hempel N: Extracellular glutathione peroxidase GPx3 and its role in cancer. Cancers (Basel). 12(2197)2020.PubMed/NCBI View Article : Google Scholar
9	Nirgude S and Choudhary B: Insights into the role of GPX3, a highly efficient plasma antioxidant, in cancer. Biochem Pharmacol. 184(114365)2021.PubMed/NCBI View Article : Google Scholar
10	Miess H, Dankworth B, Gouw AM, Rosenfeldt M, Schmitz W, Jiang M, Saunders B, Howell M, Downward J, Felsher DW, et al: The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma. Oncogene. 37:5435–5450. 2018.PubMed/NCBI View Article : Google Scholar
11	Wei J, Xie Q, Liu X, Wan C, Wu W, Fang K, Yao Y, Cheng P, Deng D and Liu Z: Identification the prognostic value of glutathione peroxidases expression levels in acute myeloid leukemia. Ann Transl Med. 8(678)2020.PubMed/NCBI View Article : Google Scholar
12	Liu Q, Bai W, Huang F, Tang J and Lin X: Downregulation of microRNA-196a inhibits stem cell self-renewal ability and stemness in non-small-cell lung cancer through upregulating GPX3 expression. Int J Biochem Cell Biol. 115(105571)2019.PubMed/NCBI View Article : Google Scholar
13	Worley BL, Kim YS, Mardini J, Zaman R, Leon KE, Vallur PG, Nduwumwami A, Warrick JI, Timmins PF, Kesterson JP, et al: GPx3 supports ovarian cancer progression by manipulating the extracellular redox environment. Redox Biol. 25(101051)2019.PubMed/NCBI View Article : Google Scholar
14	Cai M, Sikong Y, Wang Q, Zhu S, Pang F and Cui X: Gpx3 prevents migration and invasion in gastric cancer by targeting NFкB/Wnt5a/JNK signaling. Int J Clin Exp Pathol. 12:1194–1203. 2019.PubMed/NCBI
15	Hu Q, Chen J, Yang W, Xu M, Zhou J, Tan J and Huang T: GPX3 expression was down-regulated but positively correlated with poor outcome in human cancers. Front Oncol. 13(990551)2023.PubMed/NCBI View Article : Google Scholar
16	Chandrashekar DS, Karthikeyan SK, Korla PK, Patel H, Shovon AR, Athar M, Netto GJ, Qin ZS, Kumar S, Manne U, et al: UALCAN: An update to the integrated cancer data analysis platform. Neoplasia. 25:18–27. 2022.PubMed/NCBI View Article : Google Scholar
17	Li C, Tang Z, Zhang W, Ye Z and Liu F: GEPIA2021: Integrating multiple deconvolution-based analysis into GEPIA. Nucleic Acids Res. 49 (W1):W242–W246. 2021.PubMed/NCBI View Article : Google Scholar
18	Győrffy B: Discovery and ranking of the most robust prognostic biomarkers in serous ovarian cancer. Geroscience. 45:1889–1898. 2023.PubMed/NCBI View Article : Google Scholar
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
20	Zeng S, Pöttler M, Lan B, Grützmann R, Pilarsky C and Yang H: Chemoresistance in pancreatic cancer. Int J Mol Sci. 20(4504)2019.PubMed/NCBI View Article : Google Scholar
21	Song Y, Zou L, Li J, Shen ZP, Cai YL and Wu XD: LncRNA SNHG8 promotes the development and chemo-resistance of pancreatic adenocarcinoma. Eur Rev Med Pharmacol Sci. 22:8161–8168. 2018.PubMed/NCBI View Article : Google Scholar
22	Zhou Y, Wang K, Zhou Y, Li T, Yang M, Wang R, Chen Y, Cao M and Hu R: HEATR1 deficiency promotes pancreatic cancer proliferation and gemcitabine resistance by up-regulating Nrf2 signaling. Redox Biol. 29(101390)2020.PubMed/NCBI View Article : Google Scholar
23	Xu P, Yao J, He J, Zhao L, Wang X, Li Z and Qian J: CIP2A down regulation enhances the sensitivity of pancreatic cancer cells to gemcitabine. Oncotarget. 7:14831–14840. 2016.PubMed/NCBI View Article : Google Scholar
24	Wagner EF and Nebreda AR: Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 9:537–549. 2009.PubMed/NCBI View Article : Google Scholar
25	Kawasaki S, Ohtsuka H, Sato Y, Douchi D, Sato M, Ariake K, Masuda K, Fukase K, Mizuma M, Nakagawa K, et al: Silencing of LRRFIP1 enhances the sensitivity of gemcitabine in pancreatic cancer cells by activating JNK/c-Jun signaling. Pancreatology. 21:771–778. 2021.PubMed/NCBI View Article : Google Scholar
26	Shi J, Yang X, Kang Q, Lu J, Denzinger M, Kornmann M and Traub B: JNK inhibitor IX restrains pancreatic cancer through p53 and p21. Front Oncol. 12(1006131)2022.PubMed/NCBI View Article : Google Scholar
27	Cai J, Du S, Wang H, Xin B, Wang J, Shen W, Wei W, Guo Z and Shen X: Tenascin-C induces migration and invasion through JNK/c-Jun signalling in pancreatic cancer. Oncotarget. 8:74406–74422. 2017.PubMed/NCBI View Article : Google Scholar
28	Meggiato T, Calabrese F, De Cesare CM, Baliello E, Valente M and Del Favero G: C-JUN and CPP32 (CASPASE 3) in human pancreatic cancer: Relation to cell proliferation and death. Pancreas. 26:65–70. 2003.PubMed/NCBI View Article : Google Scholar
29	Kalli M, Li R, Mills GB, Stylianopoulos T and Zervantonakis IK: Mechanical stress signaling in pancreatic cancer cells triggers p38 MAPK- and JNK-dependent cytoskeleton remodeling and promotes cell migration via Rac1/cdc42/Myosin II. Mol Cancer Res. 20:485–497. 2022.PubMed/NCBI View Article : Google Scholar
30	Ichimaru Y, Sano M, Kajiwara I, Tobe T, Yoshioka H, Hayashi K, Ijichi H and Miyairi S: Indirubin 3'-oxime inhibits migration, invasion, and metastasis invivo in mice bearing spontaneously occurring pancreatic cancer via blocking the RAF/ERK, AKT, and SAPK/JNK pathways. Transl Oncol. 12:1574–1582. 2019.PubMed/NCBI View Article : Google Scholar
31	Liu M, Zhang Y, Yang J, Cui X, Zhou Z, Zhan H, Ding K, Tian X, Yang Z, Fung KA, et al: ZIP4 increases expression of transcription factor ZEB1 to promote integrin α3β1 signaling and inhibit expression of the gemcitabine transporter ENT1 in pancreatic cancer cells. Gastroenterology. 158:679–692.e1. 2020.PubMed/NCBI View Article : Google Scholar
32	Takahashi R, Hirata Y, Sakitani K, Nakata W, Kinoshita H, Hayakawa Y, Nakagawa H, Sakamoto K, Hikiba Y, Ijichi H, et al: Therapeutic effect of c-Jun N-terminal kinase inhibition on pancreatic cancer. Cancer Sci. 104:337–344. 2013.PubMed/NCBI View Article : Google Scholar