Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Anti-Tumor Effect of IDF-11774, an Inhibitor of Hypoxia-Inducible Factor-1, on Melanoma

  • Kim, Nan-Hyung (Department of Dermatology, Dongguk University Ilsan Hospital) ;
  • Jeong, Jong Heon (Department of Dermatology, Dongguk University Ilsan Hospital) ;
  • Park, Yu Jeong (Department of Dermatology, Dongguk University Ilsan Hospital) ;
  • Shin, Hui Young (Department of Dermatology, Dongguk University Ilsan Hospital) ;
  • Choi, Woo Kyoung (Department of Dermatology, Dongguk University Ilsan Hospital) ;
  • Lee, Kyeong (BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University) ;
  • Lee, Ai-Young (Department of Dermatology, Dongguk University Ilsan Hospital)
  • Received : 2022.05.06
  • Accepted : 2022.05.24
  • Published : 2022.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

Melanoma is one of the most aggressive skin cancers. Hypoxia contributes to the aggressiveness of melanoma by promoting cancer growth and metastasis. Upregulation of cyclin D1 can promote uncontrolled cell proliferation in melanoma, whereas stimulation of cytotoxic T cell activity can inhibit it. Epithelial mesenchymal transition (EMT) plays a critical role in melanoma metastasis. Hypoxia-inducible factor-1α (HIF-1α) is a main transcriptional mediator that regulates many genes related to hypoxia. CoCl2 is one of the most commonly used hypoxia-mimetic chemicals in cell culture. In this study, inhibitory effects of IDF-11774, an inhibitor of HIF-1α, on melanoma growth and metastasis were examined using cultured B16F10 mouse melanoma cells and nude mice transplanted with B16F10 melanoma cells in the presence or absence of CoCl2-induced hypoxia. IDF-11774 reduced HIF-1α upregulation and cell survival, but increased cytotoxicity of cultured melanoma cells under CoCl2-induced hypoxia. IDF-11774 also reduced tumor size and local invasion of B16F10 melanoma in nude mice along with HIF-1α downregulation. Expression levels of cyclin D1 in melanoma were increased by CoCl2 but decreased by IDF-11774. Apoptosis of melanoma cells and infiltration of cytotoxic T cells were increased in melanoma after treatment with IDF-11774. EMT was stimulated by CoCl2, but restored by IDF11774. Overall, IDF-11774 inhibited the growth and metastasis of B16F10 melanoma via HIF-1α downregulation. The growth of B16F10 melanoma was inhibited by cyclin D1 downregulation and cytotoxic T cell stimulation. Metastasis of B16F10 melanoma was inhibited by EMT suppression.

Keywords

Acknowledgement

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HP20C0131). This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. NRF 2018R1A5A2023127).

References

  1. Ban, H. S., Kim, B.-K., Lee, H., Kim, H. M., Harmalkar, D., Nam, M., Park, S.-K., Lee, K., Park, J.-T., Kim, I., Lee, K., Hwang, G. S. and Won, M. (2017) The novel hypoxia-inducible factor-1α inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth. Cell Death Dis. 8, e2843.
  2. Barsoum, I. B., Smallwood, C. A., Siemens, D. R. and Graham, C. H. (2014) A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res. 74, 665-674.
  3. Cheli, Y., Giuliano, S., Fenouille, N., Allegra, M., Hofman, V., Hofman, P., Bahadoran, P., Lacour, J., Tartare-Deckert, S., Bertolotto, C. and Ballotti, R. (2012) Hypoxia and MITF control metastatic behaviour in mouse and human melanoma cells. Oncogene 31, 2461-2470. https://doi.org/10.1038/onc.2011.425
  4. D'Aguanno, S., Mallone, F., Marenco, M., Del Bufalo, D. and Moramarco, A. (2021) Hypoxia-dependent drivers of melanoma progression. J. Exp. Clin. Cancer Res. 40, 159.
  5. Dratkiewicz, E., Simiczyjew, A., Mazurkiewicz, J., Zietek, M., Matkowski, R. and Nowak, D. (2021) Hypoxia and extracellular acidification as drivers of melanoma progression and drug resistance. Cells 10, 862.
  6. Gonzalez-Ruiz, L., Gonzalez-Moles, M. A., Gonzalez-Ruiz, I., Ruiz-Avila, I. and Ramos-Garcia, P. (2021) Prognostic and clinicopathological significance of CCND1/cyclin D1 upregulation in melanomas: a systematic review and comprehensive meta-analysis. Cancers 13, 1314.
  7. Kedinger, V., Meulle, A., Zounib, O., Bonnet, M.-E., Gossart, J.-B., Benoit, E., Messmer, M., Shankaranarayanan, P., Behr, J.-P., Erbacher, P. and Bolcato-Bellemin, A. L. (2013) Sticky siRNAs targeting survivin and cyclin B1 exert an antitumoral effect on melanoma subcutaneous xenografts and lung metastases. BMC Cancer 13, 338.
  8. Kim, H. J., Choi, W. J. and Lee, C. H. (2015) Phosphorylation and reorganization of keratin networks: Implications for carcinogenesis and epithelial mesenchymal transition. Biomol. Ther. (Seoul) 23, 301-312. https://doi.org/10.4062/biomolther.2015.032
  9. Koch, A., Ebert, E. V., Seitz, T., Dietrich, P., Berneburg, M., Bosserhoff, A. and Hellerbrand, C. (2020) Characterization of glycolysis-related gene expression in malignant melanoma. Pathol. Res. Pract. 216, 152752.
  10. Li, Y., Patel, S. P., Roszik, J. and Qin, Y. (2018) Hypoxia-driven immunosuppressive metabolites in the tumor microenvironment: new approaches for combinational immunotherapy. Front. Immunol. 9, 1591.
  11. Liu, A. and Curran, M. A. (2020) Tumor hypermetabolism confers resistance to immunotherapy. Semin. Cancer Biol. 65,155-163. https://doi.org/10.1016/j.semcancer.2020.01.009
  12. Mahmoud, F., Shields, B., Makhoul, I., Avaritt, N., Wong, H. K., Hutchins, L. F., Shalin, S. and Tackett, A. J. (2017) Immune surveillance in melanoma: from immune attack to melanoma escape and even counterattack. Cancer Biol. Ther. 18, 451-469. https://doi.org/10.1080/15384047.2017.1323596
  13. Malekan, M., Ebrahimzadeh, M. A. and Sheida, F. (2021) The role of Hypoxia-Inducible Factor-1alpha and its signaling in melanoma. Biomed. Pharmacother. 141, 111873.
  14. Martinez-Garcia, M. A., Riveiro-Falkenbach, E., Rodriguez-Peralto, J. L., Nagore, E., Martorell-Calatayud, A., Campos-Rodriguez, F., Farre, R., Hernandez Blasco, L., Banuls Roca, J., Chiner Vives, E., Sanchez-de-la-Torre, A., Abad Capa, J., Montserrat, J. M., Almendros, I., Perez-Gil, A., Cabriada Nuno, V., Cano-Pumarega, I., Corral Penafiel, J., Diaz Cambriles, T., Mediano, O., Dalmau Arias, J. and Gozal, D.; Spanish Sleep Network (2017) A prospective multicenter cohort study of cutaneous melanoma: clinical staging and potential associations with HIF-1α and VEGF expressions. Melanoma Res. 27, 558-564. https://doi.org/10.1097/CMR.0000000000000393
  15. Michaylira, C. Z. and Nakagawa, H. (2006) Hypoxic microenvironment as a cradle for melanoma development and progression. Cancer Biol. Ther. 5, 476-479. https://doi.org/10.4161/cbt.5.5.2749
  16. Munoz-Sanchez, J. and Chanez-Cardenas, M. E. (2019) The use of cobalt chloride as a chemical hypoxia model. J. Appl. Toxicol. 39, 556-570. https://doi.org/10.1002/jat.3749
  17. Nam, M.-W., Kim, C.-W. and Choi, K.-C. (2022) Epithelial-mesenchymal transition-inducing factors involved in the progression of lung cancers. Biomol. Ther. (Seoul) 30, 213-220. https://doi.org/10.4062/biomolther.2021.178
  18. Nowak-Stepniowska, A., Osuchowska, P. N., Fiedorowicz, H. and Trafny, E. A. (2022) Insight in hypoxia-mimetic agents as potential tools for mesenchymal stem cell priming in regenerative medicine. Stem Cells Int. 2022, 8775591.
  19. Pearlman, R. L., de Oca, M. K. M., Pal, H. C. and Afaq, F. (2017) Potential therapeutic targets of epithelial-mesenchymal transition in melanoma. Cancer Lett. 391, 125-140. https://doi.org/10.1016/j.canlet.2017.01.029
  20. Pio, R., Ajona, D., Ortiz-Espinosa, S., Mantovani, A. and Lambris, J. D. (2019) Complementing the cancer-immunity cycle. Front. Immunol. 10, 774.
  21. Rebecca, V. W., Somasundaram, R. and Herlyn, M. (2020) Pre-clinical modeling of cutaneous melanoma. Nat. Commun. 11, 2858.
  22. Schadendorf, D., van Akkooi, A. C., Berking, C., Griewank, K. G., Gutzmer, R., Hauschild, A., Stang, A., Roesch, A. and Ugurel, S. (2018) Melanoma. Lancet 392, 971-984. https://doi.org/10.1016/S0140-6736(18)31559-9
  23. Shrayer, D., Bogaars, H., Gersten, D., Hearing, V., Maizel, A. and Wanebo, H. (1994) Nude mouse model to study passive humoral immunotherapy directed against B16 F10 murine melanoma. J. Surg. Oncol. 57, 50-56. https://doi.org/10.1002/jso.2930570114
  24. Singh, M., Agarwal, S., Agarwal, V., Mall, S., Pancham, P. and Mani, S. (2021) Current theranostic approaches for metastatic cancers through hypoxia-induced exosomal packaged cargo. Life Sci. 286, 120017.
  25. Tchakarska, G. and Sola, B. (2020) The double dealing of cyclin D1. Cell Cycle 19, 163-178. https://doi.org/10.1080/15384101.2019.1706903
  26. Tittarelli, A., Navarrete, M., Lizana, M., Hofmann-Vega, F. and Salazar-Onfray, F. (2020) Hypoxic melanoma cells deliver microRNAs to dendritic cells and cytotoxic T lymphocytes through connexin-43 channels. Int. J. Mol. Sci. 21, 7567.
  27. Van Duijn, A., Willemsen, K. J., Van Uden, N. O., Hoyng, L., Erades, S., Koster, J., Luiten, R. M. and Bakker, W. J. (2022) A secondary role for hypoxia and HIF1 in the regulation of (IFNγ-induced) PD-L1 expression in melanoma. Cancer Immunol. Immunother. 71, 529-540. https://doi.org/10.1007/s00262-021-03007-1
  28. Vandyck, H. H., Hillen, L. M., Bosisio, F. M., van den Oord, J., Zur Hausen, A. and Winnepenninckx, V. (2021) Rethinking the biology of metastatic melanoma: a holistic approach. Cancer Metastasis Rev. 40, 603-624. https://doi.org/10.1007/s10555-021-09960-8
  29. Zou, M. Z., Liu, W. L., Li, C. X., Zheng, D. W., Zeng, J. Y., Gao, F., Ye, J. J. and Zhang, X. Z. (2018) A multifunctional biomimetic nanoplatform for relieving hypoxia to enhance chemotherapy and inhibit the PD-1/PD-L1 axis. Small 14, 1801120.