DOI QR코드

DOI QR Code

High Levels of Hyaluronic Acid Synthase-2 Mediate NRF2-Driven Chemoresistance in Breast Cancer Cells

  • Choi, Bo-Hyun (Department of Pharmacology, School of Medicine, Daegu Catholic University) ;
  • Ryoo, Ingeun (Department of Pharmacology and Integrated Research Institute for Pharmaceutical Sciences, The Catholic University of Korea) ;
  • Sim, Kyeong Hwa (Department of Pharmacology, School of Medicine, Daegu Catholic University) ;
  • Ahn, Hyeon-jin (Department of Pharmacology, School of Medicine, Daegu Catholic University) ;
  • Lee, Youn Ju (Department of Pharmacology, School of Medicine, Daegu Catholic University) ;
  • Kwak, Mi-Kyoung (Department of Pharmacology and Integrated Research Institute for Pharmaceutical Sciences, The Catholic University of Korea)
  • 투고 : 2022.05.30
  • 심사 : 2022.06.02
  • 발행 : 2022.07.01

초록

Hyaluronic acid (HA), a ligand of CD44, accumulates in some types of tumors and is responsible for tumor progression. The nuclear factor erythroid 2-like 2 (NRF2) regulates cytoprotective genes and drug transporters, which promotes therapy resistance in tumors. Previously, we showed that high levels of CD44 are associated with NRF2 activation in cancer stem like-cells. Herein, we demonstrate that HA production was increased in doxorubicin-resistant breast cancer MCF7 cells (MCF7-DR) via the upregulation of HA synthase-2 (HAS2). HA incubation increased NRF2, aldo-keto reductase 1C1 (AKR1C1), and multidrug resistance gene 1 (MDR1) levels. Silencing of HAS2 or CD44 suppressed NRF2 signaling in MCF7-DR, which was accompanied by increased doxorubicin sensitivity. The treatment with a HAS2 inhibitor, 4-methylumbelliferone (4-MU), decreased NRF2, AKR1C1, and MDR1 levels in MCF7-DR. Subsequently, 4-MU treatment inhibited sphere formation and doxorubicin resistance in MCF7-DR. The Cancer Genome Atlas (TCGA) data analysis across 32 types of tumors indicates the amplification of HAS2 gene is a common genetic alteration and is negatively correlated with the overall survival rate. In addition, high HAS2 mRNA levels are associated with increased NRF2 signaling and poor clinical outcome in breast cancer patients. Collectively, these indicate that HAS2 elevation contributes to chemoresistance and sphere formation capacity of drug-resistant MCF7 cells by activating CD44/NRF2 signaling, suggesting a potential benefit of HAS2 inhibition.

키워드

과제정보

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (2018R1A2A1A05078894, 2017R1A6A3A11030293, and 2021R1C1C1006881).

참고문헌

  1. Ahrens, T., Sleeman, J. P., Schempp, C. M., Howells, N., Hofmann, M., Ponta, H., Herrlich, P. and Simon, J. C. (2001) Soluble CD44 inhibits melanoma tumor growth by blocking cell surface CD44 binding to hyaluronic acid. Oncogene 20, 3399-3408. https://doi.org/10.1038/sj/onc/1204435
  2. Anttila, M. A., Tammi, R. H., Tammi, M. I., Syrjanen, K. J., Saarikoski, S. V. and Kosma, V. M. (2000) High levels of stromal hyaluronan predict poor disease outcome in epithelial ovarian cancer. Cancer Res. 60, 150-155.
  3. Auvinen, P., Rilla, K., Tumelius, R., Tammi, M., Sironen, R., Soini, Y., Kosma, V. M., Mannermaa, A., Viikari, J. and Tammi, R. (2014) Hyaluronan synthases (HAS1-3) in stromal and malignant cells correlate with breast cancer grade and predict patient survival. Breast Cancer Res. Treat. 143, 277-286. https://doi.org/10.1007/s10549-013-2804-7
  4. Auvinen, P., Tammi, R., Kosma, V. M., Sironen, R., Soini, Y., Mannermaa, A., Tumelius, R., Uljas, E. and Tammi, M. (2013) Increased hyaluronan content and stromal cell CD44 associate with HER2 positivity and poor prognosis in human breast cancer. Int. J. Cancer 132, 531-539. https://doi.org/10.1002/ijc.27707
  5. Auvinen, P., Tammi, R., Parkkinen, J., Tammi, M., Agren, U., Johansson, R., Hirvikoski, P., Eskelinen, M. and Kosma, V. M. (2000) Hyaluronan in peritumoral stroma and malignant cells associates with breast cancer spreading and predicts survival. Am. J. Pathol. 156, 529-536. https://doi.org/10.1016/S0002-9440(10)64757-8
  6. Balaji, S., Kim, U., Muthukkaruppan, V. and Vanniarajan, A. (2021) Emerging role of tumor microenvironment derived exosomes in therapeutic resistance and metastasis through epithelial-to-mesenchymal transition. Life Sci. 280, 119750. https://doi.org/10.1016/j.lfs.2021.119750
  7. Bartolazzi, A., Peach, R., Aruffo, A. and Stamenkovic, I. (1994) Interaction between CD44 and hyaluronate is directly implicated in the regulation of tumor development. J. Exp. Med. 180, 53-66. https://doi.org/10.1084/jem.180.1.53
  8. Bernert, B., Porsch, H. and Heldin, P. (2011) Hyaluronan synthase 2 (HAS2) promotes breast cancer cell invasion by suppression of tissue metalloproteinase inhibitor 1 (TIMP-1). J. Biol. Chem. 286, 42349-42359. https://doi.org/10.1074/jbc.M111.278598
  9. Bohrer, L. R., Chuntova, P., Bade, L. K., Beadnell, T. C., Leon, R. P., Brady, N. J., Ryu, Y., Goldberg, J. E., Schmechel, S. C., Koopmeiners, J. S., McCarthy, J. B. and Schwertfeger, K. L. (2014) Activation of the FGFR-STAT3 pathway in breast cancer cells induces a hyaluronan-rich microenvironment that licenses tumor formation. Cancer Res. 74, 374-386.
  10. Bourguignon, L. Y. (2008) Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression. Semin. Cancer Biol. 18, 251-259. https://doi.org/10.1016/j.semcancer.2008.03.007
  11. Bourguignon, L. Y., Peyrollier, K., Xia, W. and Gilad, E. (2008) Hyaluronan-CD44 interaction activates stem cell marker Nanog, Stat3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells. J. Biol. Chem. 283, 17635-17651. https://doi.org/10.1074/jbc.M800109200
  12. Bourguignon, L. Y., Shiina, M. and Li, J. J. (2014) Hyaluronan-CD44 interaction promotes oncogenic signaling, microRNA functions, chemoresistance, and radiation resistance in cancer stem cells leading to tumor progression. Adv. Cancer Res. 123, 255-275. https://doi.org/10.1016/B978-0-12-800092-2.00010-1
  13. Bourguignon, L. Y., Singleton, P. A., Zhu, H. and Diedrich, F. (2003) Hyaluronan-mediated CD44 interaction with RhoGEF and Rho kinase promotes Grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine (macrophage-colony stimulating factor) production and breast tumor progression. J. Biol. Chem. 278, 29420-29434. https://doi.org/10.1074/jbc.M301885200
  14. Bourguignon, L. Y., Singleton, P. A., Zhu, H. and Zhou, B. (2002) Hyaluronan promotes signaling interaction between CD44 and the transforming growth factor beta receptor I in metastatic breast tumor cells. J. Biol. Chem. 277, 39703-39712. https://doi.org/10.1074/jbc.M204320200
  15. Camenisch, T. D., Spicer, A. P., Brehm-Gibson, T., Biesterfeldt, J., Augustine, M. L., Calabro, A., Jr., Kubalak, S., Klewer, S. E. and McDonald, J. A. (2000) Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. J. Clin. Invest. 106, 349-360. https://doi.org/10.1172/JCI10272
  16. Chavoshinejad, R., Marei, W. F., Hartshorne, G. M. and Fouladi-Nashta, A. A. (2016) Localisation and endocrine control of hyaluronan synthase (HAS) 2, HAS3 and CD44 expression in sheep granulosa cells. Reprod. Fertil. Dev. 28, 765-775. https://doi.org/10.1071/rd14294
  17. Cho, H. Y. and Kleeberger, S. R. (2020) Mitochondrial biology in airway pathogenesis and the role of NRF2. Arch. Pharm. Res. 43, 297-320. https://doi.org/10.1007/s12272-019-01182-5
  18. Choi, B.-H., Kim, J. M. and Kwak, M.-K. (2021a) The multifaceted role of NRF2 in cancer progression and cancer stem cells maintenance. Arch. Pharm. Res. 44, 263-280. https://doi.org/10.1007/s12272-021-01316-8
  19. Choi, B.-h. and Kwak, M.-K. (2016) Shadows of NRF2 in cancer: resistance to chemotherapy. Curr. Opin. Toxicol. 1, 20-28. https://doi.org/10.1016/j.cotox.2016.08.003
  20. Choi, B. H., Ryoo, I. G., Kang, H. C. and Kwak, M. K. (2014) The sensitivity of cancer cells to pheophorbide a-based photodynamic therapy is enhanced by Nrf2 silencing. PLoS ONE 9, e107158. https://doi.org/10.1371/journal.pone.0107158
  21. Choi, S. M., Cho, Y. S., Park, G., Lee, S. K. and Chun, K. S. (2021b) Celecoxib induces apoptosis through Akt inhibition in 5-fluorouracil-resistant gastric cancer cells. Toxicol. Res. 37, 25-33. https://doi.org/10.1007/s43188-020-00044-3
  22. Chokchaitaweesuk, C., Kobayashi, T., Izumikawa, T. and Itano, N. (2019) Enhanced hexosamine metabolism drives metabolic and signaling networks involving hyaluronan production and O-GlcNAcylation to exacerbate breast cancer. Cell Death Dis. 10, 803. https://doi.org/10.1038/s41419-019-2034-y
  23. Ghatak, S., Misra, S. and Toole, B. P. (2002) Hyaluronan oligosaccharides inhibit anchorage-independent growth of tumor cells by suppressing the phosphoinositide 3-kinase/Akt cell survival pathway. J. Biol. Chem. 277, 38013-38020. https://doi.org/10.1074/jbc.M202404200
  24. Itano, N., Sawai, T., Yoshida, M., Lenas, P., Yamada, Y., Imagawa, M., Shinomura, T., Hamaguchi, M., Yoshida, Y., Ohnuki, Y., Miyauchi, S., Spicer, A. P., McDonald, J. A. and Kimata, K. (1999) Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties. J. Biol. Chem. 274, 25085-25092. https://doi.org/10.1074/jbc.274.35.25085
  25. Jung, K. A., Lee, S. and Kwak, M. K. (2017) NFE2L2/NRF2 activity is linked to mitochondria and AMP-activated protein kinase signaling in cancers through miR-181c/mitochondria-encoded cytochrome c oxidase regulation. Antioxid. Redox Signal. 27, 945-961. https://doi.org/10.1089/ars.2016.6797
  26. Kharaishvili, G., Simkova, D., Bouchalova, K., Gachechiladze, M., Narsia, N. and Bouchal, J. (2014) The role of cancer-associated fibroblasts, solid stress and other microenvironmental factors in tumor progression and therapy resistance. Cancer Cell Int. 14, 41. https://doi.org/10.1186/1475-2867-14-41
  27. Kim, T. H., Hur, E. G., Kang, S. J., Kim, J. A., Thapa, D., Lee, Y. M., Ku, S. K., Jung, Y. and Kwak, M. K. (2011) NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1α. Cancer Res. 71, 2260-2275.
  28. Knudson, W. (1996) Tumor-associated hyaluronan. Providing an extracellular matrix that facilitates invasion. Am. J. Pathol. 148, 1721-1726.
  29. Komatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y., Sou, Y. S., Ueno, I., Sakamoto, A., Tong, K. I., Kim, M., Nishito, Y., Iemura, S., Natsume, T., Ueno, T., Kominami, E., Motohashi, H., Tanaka, K. and Yamamoto, M. (2010) The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell Biol. 12, 213-223. https://doi.org/10.1038/ncb2021
  30. Lau, A., Wang, X. J., Zhao, F., Villeneuve, N. F., Wu, T., Jiang, T., Sun, Z., White, E. and Zhang, D. D. (2010) A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol. Cell. Biol. 30, 3275-3285. https://doi.org/10.1128/MCB.00248-10
  31. Lee, J. K., Lee, H. E., Yang, G., Kim, K. B., Kwack, S. J. and Lee, J. Y. (2020) Para-phenylenediamine, an oxidative hair dye ingredient, increases thymic stromal lymphopoietin and proinflammatory cytokines causing acute dermatitis. Toxicol. Res. 36, 329-336. https://doi.org/10.1007/s43188-020-00041-6
  32. Li, X., Du, X., Yao, W., Pan, Z. and Li, Q. (2020) TGF-β/SMAD4 signaling pathway activates the HAS2-HA system to regulate granulosa cell state. J. Cell. Physiol. 235, 2260-2272. https://doi.org/10.1002/jcp.29134
  33. Li, Y., Li, L., Brown, T. J. and Heldin, P. (2007) Silencing of hyaluronan synthase 2 suppresses the malignant phenotype of invasive breast cancer cells. Int. J. Cancer 120, 2557-2567. https://doi.org/10.1002/ijc.22550
  34. Lokeshwar, V. B., Lopez, L. E., Munoz, D., Chi, A., Shirodkar, S. P., Lokeshwar, S. D., Escudero, D. O., Dhir, N. and Altman, N. (2010) Antitumor activity of hyaluronic acid synthesis inhibitor 4-methylumbelliferone in prostate cancer cells. Cancer Res. 70, 2613-2623.
  35. Lokman, N. A., Price, Z. K., Hawkins, E. K., Macpherson, A. M., Oehler, M. K. and Ricciardelli, C. (2019) 4-Methylumbelliferone inhibits cancer stem cell activation and overcomes chemoresistance in ovarian cancer. Cancers (Basel) 11, 1187. https://doi.org/10.3390/cancers11081187
  36. Marozzi, M., Parnigoni, A., Negri, A., Viola, M., Vigetti, D., Passi, A., Karousou, E. and Rizzi, F. (2021) Inflammation, extracellular matrix remodeling, and proteostasis in tumor microenvironment. Int. J. Mol. Sci. 22, 8102. https://doi.org/10.3390/ijms22158102
  37. Meng, E., Long, B., Sullivan, P., McClellan, S., Finan, M. A., Reed, E., Shevde, L. and Rocconi, R. P. (2012) CD44+/CD24- ovarian cancer cells demonstrate cancer stem cell properties and correlate to survival. Clin. Exp. Metastasis 29, 939-948. https://doi.org/10.1007/s10585-012-9482-4
  38. Ohashi, R., Takahashi, F., Cui, R., Yoshioka, M., Gu, T., Sasaki, S., Tominaga, S., Nishio, K., Tanabe, K. K. and Takahashi, K. (2007) Interaction between CD44 and hyaluronate induces chemoresistance in non-small cell lung cancer cell. Cancer Lett. 252, 225-234. https://doi.org/10.1016/j.canlet.2006.12.025
  39. Okuda, H., Kobayashi, A., Xia, B., Watabe, M., Pai, S. K., Hirota, S., Xing, F., Liu, W., Pandey, P. R., Fukuda, K., Modur, V., Ghosh, A., Wilber, A. and Watabe, K. (2012) Hyaluronan synthase HAS2 promotes tumor progression in bone by stimulating the interaction of breast cancer stem-like cells with macrophages and stromal cells. Cancer Res. 72, 537-547.
  40. Orgaz, J. L., Pandya, P., Dalmeida, R., Karagiannis, P., Sanchez-Laorden, B., Viros, A., Albrengues, J., Nestle, F. O., Ridley, A. J., Gaggioli, C., Marais, R., Karagiannis, S. N. and Sanz-Moreno, V. (2014) Diverse matrix metalloproteinase functions regulate cancer amoeboid migration. Nat. Commun. 5, 4255. https://doi.org/10.1038/ncomms5255
  41. Otsuki, A. and Yamamoto, M. (2020) Cis-element architecture of Nrf2-sMaf heterodimer binding sites and its relation to diseases. Arch. Pharm. Res. 43, 275-285. https://doi.org/10.1007/s12272-019-01193-2
  42. Pan, B., Toms, D. and Li, J. (2018) MicroRNA-574 suppresses oocyte maturation via targeting hyaluronan synthase 2 in porcine cumulus cells. Am. J. Physiol. Cell Physiol. 314, C268-C277. https://doi.org/10.1152/ajpcell.00065.2017
  43. Peterson, R. M., Yu, Q., Stamenkovic, I. and Toole, B. P. (2000) Perturbation of hyaluronan interactions by soluble CD44 inhibits growth of murine mammary carcinoma cells in ascites. Am. J. Pathol. 156, 2159-2167. https://doi.org/10.1016/S0002-9440(10)65086-9
  44. Poukka, M., Bykachev, A., Siiskonen, H., Tyynela-Korhonen, K., Auvinen, P., Pasonen-Seppanen, S. and Sironen, R. (2016) Decreased expression of hyaluronan synthase 1 and 2 associates with poor prognosis in cutaneous melanoma. BMC Cancer 16, 313. https://doi.org/10.1186/s12885-016-2344-8
  45. Preca, B. T., Bajdak, K., Mock, K., Lehmann, W., Sundararajan, V., Bronsert, P., Matzge-Ogi, A., Orian-Rousseau, V., Brabletz, S., Brabletz, T., Maurer, J. and Stemmler, M. P. (2017) A novel ZEB1/HAS2 positive feedback loop promotes EMT in breast cancer. Oncotarget 8, 11530-11543. https://doi.org/10.18632/oncotarget.14563
  46. Prestwich, G. D. (2011) Hyaluronic acid-based clinical biomaterials derived for cell and molecule delivery in regenerative medicine. J. Control. Release 155, 193-199. https://doi.org/10.1016/j.jconrel.2011.04.007
  47. Qin, Z., Dai, L., Bratoeva, M., Slomiany, M. G., Toole, B. P. and Parsons, C. (2011) Cooperative roles for emmprin and LYVE-1 in the regulation of chemoresistance for primary effusion lymphoma. Leukemia 25, 1598-1609. https://doi.org/10.1038/leu.2011.144
  48. Ropponen, K., Tammi, M., Parkkinen, J., Eskelinen, M., Tammi, R., Lipponen, P., Agren, U., Alhava, E. and Kosma, V. M. (1998) Tumor cell-associated hyaluronan as an unfavorable prognostic factor in colorectal cancer. Cancer Res. 58, 342-347.
  49. Ryoo, I. G., Choi, B. H., Ku, S. K. and Kwak, M. K. (2018) High CD44 expression mediates p62-associated NFE2L2/NRF2 activation in breast cancer stem cell-like cells: implications for cancer stem cell resistance. Redox Biol. 17, 246-258. https://doi.org/10.1016/j.redox.2018.04.015
  50. Ryu, D., Lee, J. H. and Kwak, M. K. (2020) NRF2 level is negatively correlated with TGF-β1-induced lung cancer motility and migration via NOX4-ROS signaling. Arch. Pharm. Res. 43, 1297-1310. https://doi.org/10.1007/s12272-020-01298-z
  51. Sheng, Y., Cao, M., Liu, Y., He, Y., Zhang, G., Du, Y., Gao, F. and Yang, C. (2021) Hyaluronan synthase 2 (HAS2) regulates cell phenotype and invadopodia formation in luminal-like breast cancer cells. Mol. Cell. Biochem. 476, 3383-3391. https://doi.org/10.1007/s11010-021-04165-7
  52. Shibata, T., Ohta, T., Tong, K. I., Kokubu, A., Odogawa, R., Tsuta, K., Asamura, H., Yamamoto, M. and Hirohashi, S. (2008) Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc. Natl. Acad. Sci. U.S.A. 105, 13568-13573. https://doi.org/10.1073/pnas.0806268105
  53. Son, B., Lee, S., Youn, H., Kim, E., Kim, W. and Youn, B. (2017) The role of tumor microenvironment in therapeutic resistance. Oncotarget 8, 3933-3945. https://doi.org/10.18632/oncotarget.13907
  54. Sun, Y. (2016) Tumor microenvironment and cancer therapy resistance. Cancer Lett. 380, 205-215. https://doi.org/10.1016/j.canlet.2015.07.044
  55. Takaishi, S., Okumura, T., Tu, S., Wang, S. S., Shibata, W., Vigneshwaran, R., Gordon, S. A., Shimada, Y. and Wang, T. C. (2009) Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells 27, 1006-1020. https://doi.org/10.1002/stem.30
  56. Tiainen, S., Oikari, S., Tammi, M., Rilla, K., Hamalainen, K., Tammi, R., Kosma, V. M. and Auvinen, P. (2016) High extent of O-GlcNAcylation in breast cancer cells correlates with the levels of HAS enzymes, accumulation of hyaluronan, and poor outcome. Breast Cancer Res. Treat. 160, 237-247. https://doi.org/10.1007/s10549-016-3996-4
  57. Udabage, L., Brownlee, G. R., Nilsson, S. K. and Brown, T. J. (2005) The over-expression of HAS2, Hyal-2 and CD44 is implicated in the invasiveness of breast cancer. Exp. Cell Res. 310, 205-217. https://doi.org/10.1016/j.yexcr.2005.07.026
  58. Wang, X. J., Sun, Z., Villeneuve, N. F., Zhang, S., Zhao, F., Li, Y., Chen, W., Yi, X., Zheng, W., Wondrak, G. T., Wong, P. K. and Zhang, D. D. (2008) Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis 29, 1235-1243. https://doi.org/10.1093/carcin/bgn095
  59. Weigel, P. H., Hascall, V. C. and Tammi, M. (1997) Hyaluronan synthases. J. Biol. Chem. 272, 13997-14000. https://doi.org/10.1074/jbc.272.22.13997
  60. Yang, C., Sheng, Y., Shi, X., Liu, Y., He, Y., Du, Y., Zhang, G. and Gao, F. (2020) CD44/HA signaling mediates acquired resistance to a PI3Kα inhibitor. Cell Death Dis 11, 831. https://doi.org/10.1038/s41419-020-03037-0
  61. Yu, M., Zhang, K., Wang, S., Xue, L., Chen, Z., Feng, N., Ning, C., Wang, L., Li, J., Zhang, B., Yang, C. and Zhang, Z. (2021) Increased SPHK1 and HAS2 expressions correlate to poor prognosis in pancreatic cancer. Biomed. Res. Int. 2021, 8861766.
  62. Yu, Q. and Stamenkovic, I. (1999) Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev. 13, 35-48. https://doi.org/10.1101/gad.13.1.35