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 DPP4high tumors treated with DPP4 inhibitors. This study provides new insights into TKI resistance and drug repositioning of DPP4 inhibitor as a promising strategy for advanced RCC.
Subscribe to Journal
Get full journal access for 1 year
only $7.98 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
All other data are available in the Article, Supplementary Information or available from the authors upon reasonable request.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.
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.
Ghatalia P, Zibelman M, Geynisman DM, Plimack ER. Checkpoint Inhibitors for the Treatment of Renal Cell Carcinoma. Curr Treat Options Oncol. 2017;18:7.
Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med. 2011;17:313–9.
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.
Corro C, Moch H. Biomarker discovery for renal cancer stem cells. J Pathol Clin Res. 2018;4:3–18.
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.
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.
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.
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.
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.
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.
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.
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.
Röhrborn D, Wronkowitz N, Eckel J. DPP4 in Diabetes. Front Immunol. 2015;6:386.
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.
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.
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.
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.
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.
Wasserman WW, Sandelin A. Applied bioinformatics for the identification of regulatory elements. Nat Rev Genet. 2004;5:276–87.
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.
Holst JJ, Vilsbøll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009;297:127–36.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
We thank S. Kitayama, W. Sato, S. Shiba, Y. Okada, and S. Aoki for their technical support and valuable comments. This study was supported by the Support Project of Strategic Research Center in Private Universities from the MEXT (to SI), the Practical Research for Innovative Cancer Control (JP18ck0106194 to KI) and the Project for Cancer Research and Therapeutic Evolution (P-CREATE, JP18cm0106144 to SI) from Japan Agency for Medical Research and Development (AMED), and grants from the Japan Society for the Promotion of Science (15K15353 and 20K21667 to SI, and 17H04205 to K-HI) and the Vehicle Racing Commemorative Foundation (to K-HI).
Conflict of interest
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Kamada, S., Namekawa, T., Ikeda, K. et al. Functional inhibition of cancer stemness-related protein DPP4 rescues tyrosine kinase inhibitor resistance in renal cell carcinoma. Oncogene 40, 3899–3913 (2021). https://doi.org/10.1038/s41388-021-01822-5