FBW7 increases the chemosensitivity of pancreatic cancer cells to gemcitabine through upregulation of ENT1

Hu,Qiangsheng; Qin,Yi; Zhang,Bo; Liang,Chen; Ji,Shunrong; Shi,Si; Xu,Wenyan; Xiang,Jinfeng; Liang,Dingkong; Ni,Quanxing; Yu,Xianjun; Xu,Jin

doi:10.3892/or.2017.5856

FBW7 increases the chemosensitivity of pancreatic cancer cells to gemcitabine through upregulation of ENT1

Authors:
- Qiangsheng Hu
- Yi Qin
- Bo Zhang
- Chen Liang
- Shunrong Ji
- Si Shi
- Wenyan Xu
- Jinfeng Xiang
- Dingkong Liang
- Quanxing Ni
- Xianjun Yu
- Jin Xu
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Affiliations: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
Published online on: July 28, 2017 https://doi.org/10.3892/or.2017.5856
Pages: 2069-2077
Copyright: © Hu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

F-box and WD repeat domain-containing 7 (FBW7) has been characterized as a tumor suppressor, and its mutation or decreased expression has been observed in many types of human cancers. Our recent studies have uncovered that in pancreatic cancer, the KRAS mutation decreased FBW7 expression through phosphorylation and subsequent ubiquitination. Moreover, FBW7 inhibited aerobic glycolysis in pancreatic cancer via induction of thioredoxin-interacting protein (TXNIP), a mitochondrial localized tumor suppressor. The roles of FBW7 in anti-apoptosis and drug resistance via proteosomal degradation of myeloid cell leukemia-1 (MCL-1), which is an anti-apoptotic factor have been reported. However, the role of FBW7 in the chemotherapeutic resistance of pancreatic cancer to gemcitabine has seldom been reported. In the present study, we demonstrated that overexpression of FBW7 in pancreatic cancer cells rendered increased sensitivity to gemcitabine. Mechanistically, FBW7 promoted gemcitabine sensitivity via upregulation of equilibrative nucleoside transporter 1 (ENT1) at the protein level rather than the transcriptional level. In depth analysis demonstrated that the ENT1 protein level could be increased by lysosome inhibition. Taken together, our results demonstrated that FBW7 could be a target for improving the therapeutic efficacy of gemcitabine by induction of ENT1.

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1	Vincent A, Herman J, Schulick R, Hruban RH and Goggins M: Pancreatic cancer. Lancet. 378:607–620. 2011. View Article : Google Scholar : PubMed/NCBI
2	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
3	Saif MW: Advanced stage pancreatic cancer: Novel therapeutic options. Expert Rev Clin Pharmacol. 7:487–498. 2014. View Article : Google Scholar : PubMed/NCBI
4	Cid-Arregui A and Juarez V: Perspectives in the treatment of pancreatic adenocarcinoma. World J Gastroenterol. 21:9297–9316. 2015. View Article : Google Scholar : PubMed/NCBI
5	Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, et al: Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 364:1817–1825. 2011. View Article : Google Scholar : PubMed/NCBI
6	Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, et al: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 369:1691–1703. 2013. View Article : Google Scholar : PubMed/NCBI
7	Wang Z, Inuzuka H, Zhong J, Wan L, Fukushima H, Sarkar FH and Wei W: Tumor suppressor functions of FBW7 in cancer development and progression. FEBS Lett. 586:1409–1418. 2012. View Article : Google Scholar : PubMed/NCBI
8	Min SH, Lau AW, Lee TH, Inuzuka H, Wei S, Huang P, Shaik S, Lee DY, Finn G, Balastik M, et al: Negative regulation of the stability and tumor suppressor function of Fbw7 by the Pin1 prolyl isomerase. Mol Cell. 46:771–783. 2012. View Article : Google Scholar : PubMed/NCBI
9	Akhoondi S, Sun D, von der Lehr N, Apostolidou S, Klotz K, Maljukova A, Cepeda D, Fiegl H, Dafou D, Marth C, et al: FBXW7/hCDC4 is a general tumor suppressor in human cancer. Cancer Res. 67:9006–9012. 2007. View Article : Google Scholar : PubMed/NCBI
10	Akhoondi S, Lindström L, Widschwendter M, Corcoran M, Bergh J, Spruck C, Grandér D and Sangfelt O: Inactivation of FBXW7/hCDC4-β expression by promoter hypermethylation is associated with favorable prognosis in primary breast cancer. Breast Cancer Res. 12:R1052010. View Article : Google Scholar : PubMed/NCBI
11	Ji S, Qin Y, Shi S, Liu X, Hu H, Zhou H, Gao J, Zhang B, Xu W, Liu J, et al: ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer. Cell Res. 25:561–573. 2015. View Article : Google Scholar : PubMed/NCBI
12	Ji S, Qin Y, Liang C, Huang R, Shi S, Liu J, Jin K, Liang D, Xu W, Zhang B, et al: FBW7 (F-box and WD repeat domain- containing 7) negatively regulates glucose metabolism by targeting the c-Myc/TXNIP (thioredoxin-binding protein) axis in pancreatic cancer. Clin Cancer Res. 22:3950–3960. 2016. View Article : Google Scholar : PubMed/NCBI
13	Liang C, Qin Y, Zhang B, Ji S, Shi S, Xu W, Liu J, Xiang J, Liang D, Hu Q, et al: Oncogenic KRAS targets MUC16/CA125 in pancreatic ductal adenocarcinoma. Mol Cancer Res. 15:201–212. 2017. View Article : Google Scholar : PubMed/NCBI
14	Maréchal R, Bachet JB, Mackey JR, Dalban C, Demetter P, Graham K, Couvelard A, Svrcek M, Bardier-Dupas A, Hammel P, et al: Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma. Gastroenterology. 143:664–674. 2012. View Article : Google Scholar : PubMed/NCBI
15	Nordh S, Ansari D and Andersson R: hENT1 expression is predictive of gemcitabine outcome in pancreatic cancer: A systematic review. World J Gastroenterol. 20:8482–8490. 2014. View Article : Google Scholar : PubMed/NCBI
16	Spratlin J, Sangha R, Glubrecht D, Dabbagh L, Young JD, Dumontet C, Cass C, Lai R and Mackey JR: The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin Cancer Res. 10:6956–6961. 2004. View Article : Google Scholar : PubMed/NCBI
17	Plunkett W, Huang P, Searcy CE and Gandhi V: Gemcitabine: Preclinical pharmacology and mechanisms of action. Semin Oncol. 23 Suppl 10:S3–S15. 1996.
18	Kourie HR, Gharios J, Elkarak F, Antoun J and Ghosn M: Is metastatic pancreatic cancer an untargetable malignancy? World J Gastrointest Oncol. 8:297–304. 2016. View Article : Google Scholar : PubMed/NCBI
19	Ertel F, Nguyen M, Roulston A and Shore GC: Programming cancer cells for high expression levels of Mcl1. EMBO Rep. 14:328–336. 2013. View Article : Google Scholar : PubMed/NCBI
20	Wertz IE, Kusam S, Lam C, Okamoto T, Sandoval W, Anderson DJ, Helgason E, Ernst JA, Eby M, Liu J, et al: Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature. 471:110–114. 2011. View Article : Google Scholar : PubMed/NCBI
21	Lucchetti C, Rizzolio F, Castronovo M and Toffoli G: Research highlights. MCL1 and FBW7 as new predictive candidate biomarkers of anti-tubulin agents. Pharmacogenomics. 12:1379–1380. 2011. View Article : Google Scholar : PubMed/NCBI
22	Kirkegaard T and Jäättelä M: Lysosomal involvement in cell death and cancer. Biochim Biophys Acta. 1793:746–754. 2009. View Article : Google Scholar : PubMed/NCBI
23	Guicciardi ME, Leist M and Gores GJ: Lysosomes in cell death. Oncogene. 23:2881–2890. 2004. View Article : Google Scholar : PubMed/NCBI
24	Maxfield FR and McGraw TE: Endocytic recycling. Nat Rev Mol Cell Biol. 5:121–132. 2004. View Article : Google Scholar : PubMed/NCBI
25	Seixas E, Barros M, Seabra MC and Barral DC: Rab and Arf proteins in genetic diseases. Traffic. 14:871–885. 2013. View Article : Google Scholar : PubMed/NCBI
26	D'Souza-Schorey C and Chavrier P: ARF proteins: Roles in membrane traffic and beyond. Nat Rev Mol Cell Biol. 7:347–358. 2006. View Article : Google Scholar : PubMed/NCBI
27	Le Roy C and Wrana JL: Clathrin- and non-clathrin-mediated endocytic regulation of cell signalling. Nat Rev Mol Cell Biol. 6:112–126. 2005. View Article : Google Scholar : PubMed/NCBI
28	Rainero E: Extracellular matrix endocytosis in controlling matrix turnover and beyond: Emerging roles in cancer. Biochem Soc Trans. 44:1347–1354. 2016. View Article : Google Scholar : PubMed/NCBI
29	White E, Mehnert JM and Chan CS: Autophagy, metabolism, and cancer. Clin Cancer Res. 21:5037–5046. 2015. View Article : Google Scholar : PubMed/NCBI
30	Peng K, Dai Q, Wei J, Shao G, Sun A, Yang W and Lin Q: Stress-induced endocytosis and degradation of epidermal growth factor receptor are two independent processes. Cancer Cell Int. 16:252016. View Article : Google Scholar : PubMed/NCBI
31	Sorkin A: Internalization of the epidermal growth factor receptor: Role in signalling. Biochem Soc Trans. 29:480–484. 2001. View Article : Google Scholar : PubMed/NCBI
32	Joffre C, Barrow R, Ménard L, Calleja V, Hart IR and Kermorgant S: A direct role for Met endocytosis in tumorigenesis. Nat Cell Biol. 13:827–837. 2011. View Article : Google Scholar : PubMed/NCBI
33	Seton-Rogers S: Signalling: Location, location, location. Nat Rev Cancer. 11:462–463. 2011. View Article : Google Scholar : PubMed/NCBI
34	Clague MJ: Met receptor: A moving target. Sci Signal. 4:pe402011. View Article : Google Scholar : PubMed/NCBI
35	Mosesson Y, Mills GB and Yarden Y: Derailed endocytosis: An emerging feature of cancer. Nat Rev Cancer. 8:835–850. 2008. View Article : Google Scholar : PubMed/NCBI
36	Tardy C, Codogno P, Autefage H, Levade T and Andrieu-Abadie N: Lysosomes and lysosomal proteins in cancer cell death (new players of an old struggle). Biochim Biophys Acta. 1765:101–125. 2006.PubMed/NCBI
37	Appelqvist H, Wäster P, Kågedal K and Öllinger K: The lysosome: From waste bag to potential therapeutic target. J Mol Cell Biol. 5:214–226. 2013. View Article : Google Scholar : PubMed/NCBI