Functional inhibition of cancer stemness-related protein DPP4 rescues tyrosine kinase inhibitor resistance in renal cell carcinoma.
Aged
Aged, 80 and over
Animals
Carcinoma, Renal Cell
/ drug therapy
Cell Line, Tumor
Diabetes Mellitus, Type 2
/ drug therapy
Dipeptidyl Peptidase 4
/ chemistry
Dipeptidyl-Peptidase IV Inhibitors
/ pharmacology
Drug Resistance, Neoplasm
Female
Humans
Kidney Neoplasms
/ drug therapy
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Protein Kinase Inhibitors
/ pharmacology
Sitagliptin Phosphate
/ pharmacology
Spheroids, Cellular
Sunitinib
/ pharmacology
Survival Rate
Xenograft Model Antitumor Assays
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
23
12
2020
accepted:
26
04
2021
revised:
18
04
2021
pubmed:
12
5
2021
medline:
13
1
2022
entrez:
11
5
2021
Statut:
ppublish
Résumé
Tyrosine kinase inhibitors (TKIs) are used as targeted drugs for advanced renal cell carcinoma (RCC), although most cases eventually progress by acquiring resistance. Cancer stemness plays critical roles in tumor aggressiveness and therapeutic resistance, and dipeptidyl peptidase IV (DPP4) has been recently identified as a cancer stemness-related protein. A question arises whether DPP4 contributes to TKI efficacy in RCC. We established patient-derived RCC spheroids and showed that DPP4 expression is associated with stemness-related gene expression. TKI sunitinib resistance was rescued by DPP4 inhibition using sitagliptin or specific siRNAs in RCC cells and tumors. DPP4 expression can be inducible by retinoic acid and repressed by ALDH1A inhibition. Among type 2 diabetes patients with clinical RCC tumors, higher TKI efficacy is observed in those bearing DPP4
Identifiants
pubmed: 33972682
doi: 10.1038/s41388-021-01822-5
pii: 10.1038/s41388-021-01822-5
doi:
Substances chimiques
Dipeptidyl-Peptidase IV Inhibitors
0
Protein Kinase Inhibitors
0
DPP4 protein, human
EC 3.4.14.5
Dipeptidyl Peptidase 4
EC 3.4.14.5
Sitagliptin Phosphate
TS63EW8X6F
Sunitinib
V99T50803M
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3899-3913Références
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.
pubmed: 29313949
doi: 10.3322/caac.21442
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.
pubmed: 30207593
doi: 10.3322/caac.21492
Ghatalia P, Zibelman M, Geynisman DM, Plimack ER. Checkpoint Inhibitors for the Treatment of Renal Cell Carcinoma. Curr Treat Options Oncol. 2017;18:7.
pubmed: 28210995
doi: 10.1007/s11864-017-0458-0
Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med. 2011;17:313–9.
pubmed: 21386835
doi: 10.1038/nm.2304
Fendler A, Bauer D, Busch J, Jung K, Wulf-Goldenberg A, Kunz S, et al. Inhibiting WNT and NOTCH in renal cancer stem cells and the implications for human patients. Nat Commun. 2020;11:929.
pubmed: 32066735
pmcid: 7026425
doi: 10.1038/s41467-020-14700-7
Corro C, Moch H. Biomarker discovery for renal cancer stem cells. J Pathol Clin Res. 2018;4:3–18.
pubmed: 29416873
pmcid: 5783955
doi: 10.1002/cjp2.91
Varna M, Gapihan G, Feugeas JP, Ratajczak P, Tan S, Ferreira I, et al. Stem cells increase in numbers in perinecrotic areas in human renal cancer. Clin Cancer Res. 2015;21:916–24.
pubmed: 25501128
doi: 10.1158/1078-0432.CCR-14-0666
Luo L, Liang Y, Ding X, Ma X, Zhang G, Sun L, et al. Significance of cyclooxygenase-2, prostaglandin E2 and CD133 levels in sunitinib-resistant renal cell carcinoma. Oncol Lett. 2019;18:1442–50.
pubmed: 31423209
pmcid: 6607046
Oguro T, Ishibashi K, Sugino T, Hashimoto K, Tomita S, Takahashi N, et al. Humanised antihuman IL-6R antibody with interferon inhibits renal cell carcinoma cell growth in vitro and in vivo through suppressed SOCS3 expression. Eur J Cancer. 2013;49:1715–24.
pubmed: 23274199
doi: 10.1016/j.ejca.2012.11.038
Ishibashi K, Haber T, Breuksch I, Gebhard S, Sugino T, Kubo H, et al. Overriding TKI resistance of renal cell carcinoma by combination therapy with IL-6 receptor blockade. Oncotarget 2017;8:55230–45.
pubmed: 28903416
pmcid: 5589655
doi: 10.18632/oncotarget.19420
Pang R, Law WL, Chu ACY, Poon JT, Lam CSC, Chow AKM, et al. A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell. 2010;6:603–15.
pubmed: 20569697
doi: 10.1016/j.stem.2010.04.001
Ghani FI, Yamazaki H, Iwata S, Okamoto T, Aoe K, Okabe K, et al. Identification of cancer stem cell markers in human malignant mesothelioma cells. Biochem Biophys Res Commun. 2011;404:735–42.
pubmed: 21163253
doi: 10.1016/j.bbrc.2010.12.054
Inamoto T, Yamochi T, Ohnuma K, Iwata S, Kina S, Inamoto S, et al. Anti-CD26 monoclonal antibody-mediated G1-S arrest of human renal clear cell carcinoma Caki-2 is associated with retinoblastoma substrate dephosphorylation, cyclin-dependent kinase 2 reduction, p27(kip1) enhancement, and disruption of binding to the extracellular matrix. Clin Cancer Res. 2006;12:3470–7.
pubmed: 16740772
doi: 10.1158/1078-0432.CCR-06-0361
Angevin E, Isambert N, Trillet-Lenoir V, You B, Alexandre J, Zalcman G, et al. First-in-human phase 1 of YS110, a monoclonal antibody directed against CD26 in advanced CD26-expressing cancers. Br J Cancer. 2017;116:1126–34.
pubmed: 28291776
pmcid: 5418443
doi: 10.1038/bjc.2017.62
Röhrborn D, Wronkowitz N, Eckel J. DPP4 in Diabetes. Front Immunol. 2015;6:386.
pubmed: 26284071
pmcid: 4515598
doi: 10.3389/fimmu.2015.00386
Ishiguro T, Sato A, Ohata H, Ikarashi Y, Takahashi RU, Ochiya T, et al. Establishment and Characterization of an In Vitro Model of Ovarian Cancer Stem-like Cells with an Enhanced Proliferative Capacity. Cancer Res. 2016;76:150–60.
pubmed: 26669863
doi: 10.1158/0008-5472.CAN-15-0361
Namekawa T, Ikeda K, Horie-Inoue K, Suzuki T, Okamoto K, Ichikawa T, et al. ALDH1A1 in patient-derived bladder cancer spheroids activates retinoic acid signaling leading to TUBB3 overexpression and tumor progression. Int J Cancer. 2019;146:1099–113.
pubmed: 31187490
doi: 10.1002/ijc.32505
Shiba S, Ikeda K, Suzuki T, Shintani D, Okamoto K, Horie-Inoue K, et al. Hormonal Regulation of Patient-Derived Endometrial Cancer Stem-like Cells Generated by Three-Dimensional Culture. Endocrinology. 2019;160:1895–906.
pubmed: 31265065
doi: 10.1210/en.2019-00362
Pinheiro MM, Stoppa CL, Valduga CJ, Okuyama CE, Gorjao R, Pereira RMS, et al. Sitagliptin inhibit human lymphocytes proliferation and Th1/Th17 differentiation in vitro. Eur J Pham Sci. 2017;100:17–24.
doi: 10.1016/j.ejps.2016.12.040
Sakai I, Miyake H, Fujisawa M. Acquired resistance to sunitinib in human renal cell carcinoma cells is mediated by constitutive activation of signal transduction pathways associated with tumour cell proliferation. BJU Int. 2013;112:E211–220.
pubmed: 23305097
doi: 10.1111/j.1464-410X.2012.11655.x
Wasserman WW, Sandelin A. Applied bioinformatics for the identification of regulatory elements. Nat Rev Genet. 2004;5:276–87.
pubmed: 15131651
doi: 10.1038/nrg1315
Bulens F, Ilbanez-Tallon I, Acker PV, De Vriese A, Nelles L, Belayew A, et al. Retinoic acid induction of human tissue-type plasminogen activator gene expression via a direct repeat element (DR5) located at -7 kilobases. J Biol Chem. 1995;270:7167–75.
pubmed: 7706255
doi: 10.1074/jbc.270.13.7167
Holst JJ, Vilsbøll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009;297:127–36.
pubmed: 18786605
doi: 10.1016/j.mce.2008.08.012
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.
pubmed: 19097774
doi: 10.1016/j.ejca.2008.10.026
Sinha R, Winer AG, Chevinsky M, Jakubowski C, Chen YB, Dong Y, et al. Analysis of renal cancer cell lines from two major resources enables genomics-guided cell line selection. Nat Commun. 2017;8:15165.
pubmed: 28489074
pmcid: 5436135
doi: 10.1038/ncomms15165
Enz N, Vliegen G, De Meester I, Jungraithmayr W. CD26/DPP4 - a potential biomarker and target for cancer therapy. Pharm Ther. 2019;198:135–59.
doi: 10.1016/j.pharmthera.2019.02.015
Varona A, Blanco L, Perez I, Gil J, Irazusta J, Lopez JI, et al. Expression and activity profiles of DPP IV/CD26 and NEP/CD10 glycoproteins in the human renal cancer are tumor-type dependent. BMC Cancer. 2010;10:193.
pubmed: 20459800
pmcid: 2876082
doi: 10.1186/1471-2407-10-193
Uhlen M, Zhang C, Lee S, Sjostedt E, Fagerberg L, Bidkhori G, et al. A pathology atlas of the human cancer transcriptome. Science. 2017;357:eaan2507.
pubmed: 28818916
doi: 10.1126/science.aan2507
Larrinaga G, Blanco L, Sanz B, Perez I, Gil J, Unda M, et al. The impact of peptidase activity on clear cell renal cell carcinoma survival. Am J Physiol Ren Physiol. 2012;303:F1584–1591.
doi: 10.1152/ajprenal.00477.2012
Christopherson KW 2nd, Hangoc G, Broxmeyer HE. Cell surface peptidase CD26/dipeptidylpeptidase IV regulates CXCL12/stromal cell-derived factor-1 alpha-mediated chemotaxis of human cord blood CD34+ progenitor cells. J Immunol. 2002;169:7000–8.
pubmed: 12471135
doi: 10.4049/jimmunol.169.12.7000
Miyake M, Anai S, Fujimoto K, Ohnishi S, Kuwada M, Nakai Y, et al. 5-fluorouracil enhances the antitumor effect of sorafenib and sunitinib in a xenograft model of human renal cell carcinoma. Oncol Lett. 2012;3:1195–202.
pubmed: 22783417
pmcid: 3392575
doi: 10.3892/ol.2012.662
Diaz-Montero CM, Mao FJ, Barnard J, Parker Y, Zamanian-Daryoush M, Pink JJ, et al. MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model. Br J Cancer. 2016;115:920–8.
pubmed: 27560553
pmcid: 5061902
doi: 10.1038/bjc.2016.263
Xu J, Wang J, He M, Han H, Xie W, Wang H, et al. Dipeptidyl peptidase IV (DPP-4) inhibition alleviates pulmonary arterial remodeling in experimental pulmonary hypertension. Lab Investig. 2018;98:1333–46.
pubmed: 29789684
doi: 10.1038/s41374-018-0080-1
Sun CK, Leu S, Sheu JJ, Tsai TH, Sung HC, Chen YL, et al. Paradoxical impairment of angiogenesis, endothelial function and circulating number of endothelial progenitor cells in DPP4-deficient rat after critical limb ischemia. Stem Cell Res Ther. 2013;4:31.
pubmed: 23517567
pmcid: 3706813
doi: 10.1186/scrt181
Qin CJ, Zhao LH, Zhou X, Zhang HL, Wen W, Tang L, et al. Inhibition of dipeptidyl peptidase IV prevents high fat diet-induced liver cancer angiogenesis by downregulating chemokine ligand 2. Cancer Lett. 2018;420:26–37.
pubmed: 29409972
doi: 10.1016/j.canlet.2018.01.064
Wronkowitz N, Gorgens SW, Romacho T, Villalobos LA, Ferrer CFS, Peiro C, et al. Soluble DPP4 induces inflammation and proliferation of human smooth muscle cells via protease-activated receptor 2. Biochim Biophys Acta. 2014;1842:1613–21.
pubmed: 24928308
doi: 10.1016/j.bbadis.2014.06.004
Iliopoulos D, Hirsch HA, Wang G, Struhl K. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci USA. 2011;108:1397–402.
pubmed: 21220315
pmcid: 3029760
doi: 10.1073/pnas.1018898108
Korkaya H, G-Il Kim, Davis A, Malik F, Henry NL, Ithimakin S, et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol Cell. 2012;47:570–84.
pubmed: 22819326
pmcid: 3432419
doi: 10.1016/j.molcel.2012.06.014
Huang D, Ding Y, Zhou M, Rini B, Petillo D, Qian CH, et al. Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res. 2010;70:1063–71.
pubmed: 20103651
pmcid: 3719378
doi: 10.1158/0008-5472.CAN-09-3965
Xin H, Zhang C, Hermann A, Du Y, Figlin R, Yu H. Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. Cancer Res. 2009;69:2506–13.
pubmed: 19244102
pmcid: 2664264
doi: 10.1158/0008-5472.CAN-08-4323
Hatipoglu G, Hock SW, Weiss R, Fan Z, Sehm T, Choochani A, et al. Sunitinib impedes brain tumor progression and reduces tumor-induced neurodegeneration in the microenvironment. Cancer Sci. 2015;106:160–70.
pubmed: 25458015
pmcid: 4399021
doi: 10.1111/cas.12580
Makhov P, Naito S, Haifler M, Kutikov A, Boumber Y, Uzzo RG, et al. The convergent roles of NF-κB and ER stress in sunitinib-mediated expression of pro-tumorigenic cytokines and refractory phenotype in renal cell carcinoma. Cell Death Dis. 2018;9:374.
pubmed: 29515108
pmcid: 5841329
doi: 10.1038/s41419-018-0388-1
Long Z, Cao M, Su S, Wu G, Meng F, Wu H, et al. Inhibition of hepatocyte nuclear factor 1b induces hepatic steatosis through DPP4/NOX1-mediated regulation of superoxide. Free Radic Biol Med. 2017;113:71–83.
pubmed: 28942246
pmcid: 5927376
doi: 10.1016/j.freeradbiomed.2017.09.016
Pujadas G, De Nigris V, Prattichizzo F, Sala LL, Testa R, Ceriello A. The dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin functions as antioxidant on human endothelial cells exposed to chronic hyperglycemia and metabolic high-glucose memory. Endocrine. 2017;56:509–20.
pubmed: 27530507
doi: 10.1007/s12020-016-1052-0
Adelaiye-Ogala R, Budka J, Damayanti NP, Arrington J, Ferris M, Hsu CC, et al. EZH2 Modifies Sunitinib Resistance in Renal Cell Carcinoma by Kinome Reprogramming. Cancer Res. 2017;77:6651–66.
pubmed: 28978636
pmcid: 5712262
doi: 10.1158/0008-5472.CAN-17-0899
Bauvois B, Djavaheri-Mergny M, Rouillard D, Dumont J, Wietzerbin J. Regulation of CD26/DPPIV gene expression by interferons and retinoic acid in tumor B cells. Oncogene. 2000;19:265–72.
pubmed: 10645005
doi: 10.1038/sj.onc.1203292
Fahn HJ, Lee YH, Chen MT, Huang JK, Chen KK, Chang LS. The incidence and prognostic significance of humoral hypercalcemia in renal cell carcinoma. J Urol. 1991;145:248–50.
pubmed: 1988711
doi: 10.1016/S0022-5347(17)38305-2
Papworth K, Grankvist K, Ljungberg B, Rasmuson T. Parathyroid hormone-related protein and serum calcium in patients with renal cell carcinoma. Tumour Biol. 2005;26:201–6.
pubmed: 16006777
doi: 10.1159/000086953
Onuma E, Azuma Y, Saito H, Tsunenari T, Watanabe T, Hirabayashi M, et al. Increased renal calcium reabsorption by parathyroid hormone-related protein is a causative factor in the development of humoral hypercalcemia of malignancy refractory to osteoclastic bone resorption inhibitors. Clin Cancer Res. 2005;11:4198–203.
pubmed: 15930357
doi: 10.1158/1078-0432.CCR-04-2531
Joeckel E, Haber T, Prawitt D, Junker K, Hampel C, Thuroff JW, et al. High calcium concentration in bones promotes bone metastasis in renal cell carcinomas expressing calcium-sensing receptor. Mol Cancer. 2014;13:42.
pubmed: 24576174
pmcid: 3945739
doi: 10.1186/1476-4598-13-42
Guo FJ, Jiang R, Li X, Zhang P, Han X, Liu C. Regulation of chondrocyte differentiation by IRE1α depends on its enzymatic activity. Cell Signal. 2014;26:1998–2007.
pubmed: 24863879
doi: 10.1016/j.cellsig.2014.05.008
Barreira da Silva R, Laird ME, Yatim N, Fiette L, Ingersoll MA, Albert ML. Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nat Immunol. 2015;16:850–8.
pubmed: 26075911
doi: 10.1038/ni.3201
Decalf J, Tarbell KV, Casrouge A, Price JD, Linder G, Mottez E, et al. Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post-translational modification: prospective placebo-controlled clinical studies. EMBO Mol Med. 2016;8:679–83.
pubmed: 27137491
pmcid: 4888857
doi: 10.15252/emmm.201506145
Mehta RJ, Jain RK, Leung S, Choo J, Nielsen T, Huntsman D, et al. FOXA1 is an independent prognostic marker for ER-positive breast cancer. Breast Cancer Res Treat. 2012;131:881–90.
pubmed: 21503684
doi: 10.1007/s10549-011-1482-6
Stany MP, Vathipadiekal V, Ozbun L, Stone RL, Mok SC, Xue H, et al. Identification of novel therapeutic targets in microdissected clear cell ovarian cancers. PLoS ONE. 2011;6:e21121.
pubmed: 21754983
pmcid: 3130734
doi: 10.1371/journal.pone.0021121