Lipocalin 2 inversely regulates TRAIL sensitivity through p38 MAPK-mediated DR5 regulation in colorectal cancer Corrigendum in /10.3892/ijo.2019.4748

Kim,Se-Lim; Min,In Suk; Park,Young Ran; Lee,Soo Teik; Kim,Sang-Wook

doi:10.3892/ijo.2018.4562

Lipocalin 2 inversely regulates TRAIL sensitivity through p38 MAPK-mediated DR5 regulation in colorectal cancer

Corrigendum in: /10.3892/ijo.2019.4748

Authors:
- Se-Lim Kim
- In Suk Min
- Young Ran Park
- Soo Teik Lee
- Sang-Wook Kim
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Affiliations: Department of Internal Medicine and Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju 561-712, Korea, Department of Internal Medicine and Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju 561-712, Korea
Published online on: September 14, 2018 https://doi.org/10.3892/ijo.2018.4562
Pages: 2789-2799

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Abstract

TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis through death receptors (DRs)4 and/or 5 expressed on the cell surface. Multiple clinical trials are underway to evaluate the antitumor activity of recombinant human TRAIL and agonistic antibodies to DR4 or DR5. However, their therapeutic potential is limited by the high frequency of cancer resistance. In this study, we provide evidence demonstrating the role of lipocalin 2 (LCN2) in the TRAIL-mediated apoptosis of human colorectal cancer (CRC). By analyzing the mRNA expression data of 71 CRC tissues from patients, we found that DR5 was preferentially expressed in CRC tissues with a low LCN2 expression level compared to tissues with a high LCN2 expression level. Moreover, we analyzed the association between DR5 and LCN2 expression and this analysis revealed that DR5 expression in CRC tended to be inversely associated with LCN2 expression. By contrast, no association was found between the DR4 and LCN2 expression levels. The expression patterns of LCN2 in human CRC cell lines also exhibited an inverse association with DR5 expression. The knockdown of LCN2 by siRNA in the TRAIL‑resistant CRC cells expressing high levels of LCN2 led to a significant increase in TRAIL-induced apoptosis through the upregulation of DR5 protein and mRNA expression. The mechanism through which LCN2 silencing sensitized the CRC cells to TRAIL was dependent on the extrinsic pathway of apoptosis. In addition, we identified that the knockdown of LCN2 enhanced the sensitivity of the cells to TRAIL through the p38 MAPK/CHOP-dependent upregulation of DR5. Taken together, the findings of this study suggest that LCN2 is responsible for TRAIL sensitivity and LCN2 may thus prove to be a promising target protein in DR-targeted CRC therapy.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
2	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar
3	Hara K, Beppu T, Kimura M, Fujita Y, Takata T, Nishio K and Ono N: Influence of novel supramolecular substance, [2] rotaxane, on the caspase signaling pathway in melanoma and colon cancer cells in vitro. J Pharmacol Sci. 122:153–157. 2013. View Article : Google Scholar
4	Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, et al: Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: Updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 29:2011–2019. 2011. View Article : Google Scholar : PubMed/NCBI
5	Cheng L, Ren W, Xie L, Li M, Liu J, Hu J, Liu BR and Qian XP: Anti-EGFR MoAb treatment in colorectal cancer: Limitations, controversies, and contradictories. Cancer Chemother Pharmacol. 74:1–13. 2014. View Article : Google Scholar : PubMed/NCBI
6	Hellwig CT and Rehm M: TRAIL signaling and synergy mechanisms used in TRAIL-based combination therapies. Mol Cancer Ther. 11:3–13. 2012. View Article : Google Scholar : PubMed/NCBI
7	Han B, Yao W, Oh YT, Tong JS, Li S, Deng J, Yue P, Khuri FR and Sun SY: The novel proteasome inhibitor carfilzomib activates and enhances extrinsic apoptosis involving stabilization of death receptor 5. Oncotarget. 6:17532–17542. 2015. View Article : Google Scholar : PubMed/NCBI
8	Ashkenazi A, Holland P and Eckhardt SG: Ligand-based targeting of apoptosis in cancer: The potential of recombinant human apoptosis ligand 2/Tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL). J Clin Oncol. 26:3621–3630. 2008. View Article : Google Scholar : PubMed/NCBI
9	Koehler BC, Jäger D and Schulze-Bergkamen H: Targeting cell death signaling in colorectal cancer: Current strategies and future perspectives. World J Gastroenterol. 20:1923–1934. 2014. View Article : Google Scholar : PubMed/NCBI
10	Kelley SK, Harris LA, Xie D, Deforge L, Totpal K, Bussiere J and Fox JA: Preclinical studies to predict the disposition of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand in humans: Characterization of in vivo efficacy, pharmacokinetics, and safety. J Pharmacol Exp Ther. 299:31–38. 2001.PubMed/NCBI
11	Kim SL, Liu YC, Park YR, Seo SY, Kim SH, Kim IH, Lee SO, Lee ST, Kim DG and Kim SW: Parthenolide enhances sensitivity of colorectal cancer cells to TRAIL by inducing death receptor 5 and promotes TRAIL-induced apoptosis. Int J Oncol. 46:1121–1130. 2015. View Article : Google Scholar
12	Skerra A: Lipocalins as a scaffold. Biochim Biophys Acta. 1482:337–350. 2000. View Article : Google Scholar : PubMed/NCBI
13	Yang J, Goetz D, Li JY, Wang W, Mori K, Setlik D, Du T, Erdjument-Bromage H, Tempst P, Strong R, et al: An iron delivery pathway mediated by a lipocalin. Mol Cell. 10:1045–1056. 2002. View Article : Google Scholar : PubMed/NCBI
14	Devireddy LR, Gazin C, Zhu X and Green MR: A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell. 123:1293–1305. 2005. View Article : Google Scholar : PubMed/NCBI
15	Nielsen BS, Borregaard N, Bundgaard JR, Timshel S, Sehested M and Kjeldsen L: Induction of NGAL synthesis in epithelial cells of human colorectal neoplasia and inflammatory bowel diseases. Gut. 38:414–420. 1996. View Article : Google Scholar : PubMed/NCBI
16	Sanjeevani S, Pruthi S, Kalra S, Goel A and Kalra OP: Role of neutrophil gelatinase-associated lipocalin for early detection of acute kidney injury. Int J Crit Illn Inj Sci. 4:223–228. 2014. View Article : Google Scholar : PubMed/NCBI
17	Yan C, Yuanjie T, Zhengqun X, Jiayan C and Kongdan L: Neutrophil gelatinase-associated lipocalin attenuates ischemia/ reperfusion injury in an in vitro model via autophagy activation. Med Sci Monit. 24:479–485. 2018. View Article : Google Scholar : PubMed/NCBI
18	Lee HJ, Lee EK, Lee KJ, Hong SW, Yoon Y and Kim JS: Ectopic expression of neutrophil gelatinase-associated lipocalin suppresses the invasion and liver metastasis of colon cancer cells. Int J Cancer. 118:2490–2497. 2006. View Article : Google Scholar
19	Kim SL, Lee ST, Min IS, Park YR, Lee JH, Kim DG and Kim SW: Lipocalin 2 negatively regulates cell proliferation and epithelial to mesenchymal transition through changing metabolic gene expression in colorectal cancer. Cancer Sci. 108:2176–2186. 2017. View Article : Google Scholar : PubMed/NCBI
20	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. View Article : Google Scholar
21	Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schröter M, Burns K, Mattmann C, et al: Inhibition of death receptor signals by cellular FLIP. Nature. 388:190–195. 1997. View Article : Google Scholar : PubMed/NCBI
22	Scaffidi C, Schmitz I, Zha J, Korsmeyer SJ, Krammer PH and Peter ME: Differential modulation of apoptosis sensitivity in CD95 type I and type II cells. J Biol Chem. 274:22532–22538. 1999. View Article : Google Scholar : PubMed/NCBI
23	Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, et al: Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature. 376:37–43. 1995. View Article : Google Scholar : PubMed/NCBI
24	Tewari M, Quan LT, O’Rourke K, Desnoyers S, Zeng Z, Beidler DR, Poirier GG, Salvesen GS and Dixit VM: Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell. 81:801–809. 1995. View Article : Google Scholar : PubMed/NCBI
25	Kim EY, Ryu JH and Kim AK: CAPE promotes TRAIL-induced apoptosis through the upregulation of TRAIL receptors via activation of p38 and suppression of JNK in SK-Hep1 hepatocellular carcinoma cells. Int J Oncol. 43:1291–1300. 2013. View Article : Google Scholar : PubMed/NCBI
26	Lepage C, Léger DY, Bertrand J, Martin F, Beneytout JL and Liagre B: Diosgenin induces death receptor-5 through activation of p38 pathway and promotes TRAIL-induced apoptosis in colon cancer cells. Cancer Lett. 301:193–202. 2011. View Article : Google Scholar : PubMed/NCBI
27	Ohtsuka T, Buchsbaum D, Oliver P, Makhija S, Kimberly R and Zhou T: Synergistic induction of tumor cell apoptosis by death receptor antibody and chemotherapy agent through JNK/p38 and mitochondrial death pathway. Oncogene. 22:2034–2044. 2003. View Article : Google Scholar : PubMed/NCBI
28	Pennati M, Sbarra S, De Cesare M, Lopergolo A, Locatelli SL, Campi E, Daidone MG, Carlo-Stella C, Gianni AM and Zaffaroni N: YM155 sensitizes triple-negative breast cancer to membrane-bound TRAIL through p38 MAPK- and CHOP-mediated DR5 upregulation. Int J Cancer. 136:299–309. 2015. View Article : Google Scholar
29	Wang XZ and Ron D: Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase. Science. 272:1347–1349. 1996. View Article : Google Scholar : PubMed/NCBI
30	Yamaguchi H and Wang HG: CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem. 279:45495–45502. 2004. View Article : Google Scholar : PubMed/NCBI
31	Ozören N and El-Deiry WS: Cell surface Death Receptor signaling in normal and cancer cells. Semin Cancer Biol. 13:135–147. 2003. View Article : Google Scholar : PubMed/NCBI
32	den Hollander MW, Gietema JA, de Jong S, Walenkamp AM, Reyners AK, Oldenhuis CN and de Vries EG: Translating TRAIL-receptor targeting agents to the clinic. Cancer Lett. 332:194–201. 2013. View Article : Google Scholar
33	Yoshida T, Zhang Y, Rivera Rosado LA and Zhang B: Repeated treatment with subtoxic doses of TRAIL induces resistance to apoptosis through its death receptors in MDA-MB-231 breast cancer cells. Mol Cancer Res. 7:1835–1844. 2009. View Article : Google Scholar : PubMed/NCBI
34	Jin Z, McDonald ER III, Dicker DT and El-Deiry WS: Deficient tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor transport to the cell surface in human colon cancer cells selected for resistance to TRAIL-induced apoptosis. J Biol Chem. 279:35829–35839. 2004. View Article : Google Scholar : PubMed/NCBI
35	Wainberg ZA, Messersmith WA, Peddi PF, Kapp AV, Ashkenazi A, Royer-Joo S, Portera CC and Kozloff MF: A phase 1B study of dulanermin in combination with modified FOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer. Clin Colorectal Cancer. 12:248–254. 2013. View Article : Google Scholar : PubMed/NCBI
36	Trarbach T, Moehler M, Heinemann V, Köhne CH, Przyborek M, Schulz C, Sneller V, Gallant G and Kanzler S: Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer. Br J Cancer. 102:506–512. 2010. View Article : Google Scholar : PubMed/NCBI
37	Rocha Lima CM, Bayraktar S, Flores AM, MacIntyre J, Montero A, Baranda JC, Wallmark J, Portera C, Raja R, Stern H, et al: Phase Ib study of drozitumab combined with first-line mFOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer. Cancer Invest. 30:727–731. 2012. View Article : Google Scholar : PubMed/NCBI
38	Fuchs CS, Fakih M, Schwartzberg L, Cohn AL, Yee L, Dreisbach L, Kozloff MF, Hei YJ, Galimi F, Pan Y, et al: TRAIL receptor agonist conatumumab with modified FOLFOX6 plus bevacizumab for first-line treatment of metastatic colorectal cancer: A randomized phase 1b/2 trial. Cancer. 119:4290–4298. 2013. View Article : Google Scholar : PubMed/NCBI
39	Takeda K, Stagg J, Yagita H, Okumura K and Smyth MJ: Targeting death-inducing receptors in cancer therapy. Oncogene. 26:3745–3757. 2007. View Article : Google Scholar : PubMed/NCBI
40	Do MT, Na M, Kim HG, Khanal T, Choi JH, Jin SW, Oh SH, Hwang IH, Chung YC, Kim HS, et al: Ilimaquinone induces death receptor expression and sensitizes human colon cancer cells to TRAIL-induced apoptosis through activation of ROS-ERK/p38 MAPK-CHOP signaling pathways. Food Chem Toxicol. 71:51–59. 2014. View Article : Google Scholar : PubMed/NCBI
41	Wu GS, Burns TF, McDonald ER III, Jiang W, Meng R, Krantz ID, Kao G, Gan DD, Zhou JY, Muschel R, et al: KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet. 17:141–143. 1997. View Article : Google Scholar : PubMed/NCBI
42	Ohtsuka T and Zhou T: Bisindolylmaleimide VIII enhances DR5-mediated apoptosis through the MKK4/JNK/p38 kinase and the mitochondrial pathways. J Biol Chem. 277:29294–29303. 2002. View Article : Google Scholar : PubMed/NCBI
43	Shenoy K, Wu Y and Pervaiz S: LY303511 enhances TRAIL sensitivity of SHEP-1 neuroblastoma cells via hydrogen peroxide-mediated mitogen-activated protein kinase activation and up-regulation of death receptors. Cancer Res. 69:1941–1950. 2009. View Article : Google Scholar : PubMed/NCBI
44	Bruhat A, Jousse C, Wang XZ, Ron D, Ferrara M and Fafournoux P: Amino acid limitation induces expression of CHOP, a CCAAT/enhancer binding protein-related gene, at both transcriptional and post-transcriptional levels. J Biol Chem. 272:17588–17593. 1997. View Article : Google Scholar : PubMed/NCBI
45	Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA, Strong RK, Akira S and Aderem A: Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature. 432:917–921. 2004. View Article : Google Scholar : PubMed/NCBI
46	Candido S, Maestro R, Polesel J, Catania A, Maira F, Signorelli SS, McCubrey JA and Libra M: Roles of neutrophil gelatinase-associated lipocalin (NGAL) in human cancer. Oncotarget. 5:1576–1594. 2014. View Article : Google Scholar : PubMed/NCBI