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Functional inhibition of cancer stemness-related protein DPP4 rescues tyrosine kinase inhibitor resistance in renal cell carcinoma

Oncogene volume 40, pages 3899–3913 (2021)Cite this article

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Abstract

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.

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Fig. 1: Correlation analysis between expression levels of DPP4 and cancer stemness-related genes in patient-derived renal cell carcinoma (RCC) spheroid cultures.
Fig. 2: DPP4 inhibition enhances tumor-suppressive efficacy of tyrosine kinase inhibitor sunitinib in patient-derived renal cell carcinoma (RCC) spheroid cultures.
Fig. 3: DPP4 inhibition enhances sunitinib efficacy in three-dimensional (3D) cultures of sunitinib-resistant renal cell carcinoma (RCC) cells whereas DPP4 overexpression rescues sunitinib-dependent repression of cell viability in RCC cells.
Fig. 4: Retinoic acid signaling modulates DPP4 expression in renal cell carcinoma (RCC) cells.
Fig. 5: Sitagliptin overcomes sunitinib resistance in xenograft tumors derived from ACHN cells.
Fig. 6: DPP4 inhibitor therapy potentially improves prognosis and tumor regression of renal cell carcinoma (RCC) patients treated with tyrosine kinase inhibitors (TKIs).

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All other data are available in the Article, Supplementary Information or available from the authors upon reasonable request.

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.

    Article  PubMed  Google Scholar 

  2. 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.

    Article  PubMed  Google Scholar 

  3. Ghatalia P, Zibelman M, Geynisman DM, Plimack ER. Checkpoint Inhibitors for the Treatment of Renal Cell Carcinoma. Curr Treat Options Oncol. 2017;18:7.

    Article  PubMed  Google Scholar 

  4. Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med. 2011;17:313–9.

    Article  CAS  PubMed  Google Scholar 

  5. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Corro C, Moch H. Biomarker discovery for renal cancer stem cells. J Pathol Clin Res. 2018;4:3–18.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  11. 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.

    Article  CAS  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Röhrborn D, Wronkowitz N, Eckel J. DPP4 in Diabetes. Front Immunol. 2015;6:386.

    Article  PubMed  PubMed Central  Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. 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.

    Article  PubMed  Google Scholar 

  18. 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.

    Article  CAS  PubMed  Google Scholar 

  19. 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.

    Article  CAS  Google Scholar 

  20. 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.

    Article  CAS  PubMed  Google Scholar 

  21. Wasserman WW, Sandelin A. Applied bioinformatics for the identification of regulatory elements. Nat Rev Genet. 2004;5:276–87.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

  23. Holst JJ, Vilsbøll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009;297:127–36.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  26. 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.

    Article  CAS  Google Scholar 

  27. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  28. 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.

    Article  PubMed  Google Scholar 

  29. 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.

    Article  CAS  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  31. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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.

    Article  CAS  PubMed  Google Scholar 

  34. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  35. 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.

    Article  CAS  PubMed  Google Scholar 

  36. 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.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  43. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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.

    Article  CAS  PubMed  Google Scholar 

  45. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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.

    Article  CAS  PubMed  Google Scholar 

  47. 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.

    Article  CAS  PubMed  Google Scholar 

  48. 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.

    Article  CAS  PubMed  Google Scholar 

  49. 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.

    Article  CAS  PubMed  Google Scholar 

  50. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  51. 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.

    Article  CAS  PubMed  Google Scholar 

  52. 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.

    Article  CAS  PubMed  Google Scholar 

  53. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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.

    Article  CAS  PubMed  Google Scholar 

  55. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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).

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Authors and Affiliations

  1. Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan

    Shuhei Kamada, Takeshi Namekawa, Kazuhiro Ikeda, Kuniko Horie-Inoue & Satoshi Inoue

  2. Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan

    Shuhei Kamada, Takeshi Namekawa & Tomohiko Ichikawa

  3. Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Miyagi, Japan

    Takashi Suzuki

  4. Department of Urology, Saitama Medical Center, Saitama Medical University, Saitama, Japan

    Makoto Kagawa, Hideki Takeshita, Akihiro Yano & Satoru Kawakami

  5. Division of Cancer Differentiation, National Cancer Center Research Institute, Tokyo, Japan

    Koji Okamoto

  6. Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

    Satoshi Inoue

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  1. Shuhei Kamada
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Contributions

Study concepts: KI, KH-I, KO, SI. Study design: KI, KH-I, KO, SI. Data acquisition: MK, HT, AY, SK, KI. Quality control of data and algorithms: SK, TN, KO, KI, KH-I. Data analysis and interpretation: SK, TS, KI. Statistical analysis: SK, TS, KI. Paper preparation: SK, KI, KH-I, Inoue S. Paper editing: SK, KI, KH-I, TN, TS. Paper review: KO, TI, AY, SK, SI.

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Correspondence to Satoshi Inoue.

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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

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