Welcome to Francis Academic Press

International Journal of Frontiers in Medicine, 2022, 4(3); doi: 10.25236/IJFM.2022.040307.

Tunicamycin Attenuates Cardiac Automaticity by Reducing HCN Current

Author(s)

Juanjuan Zhang1,2,3, Weizhe Liu4, Yue Zhang1, Hongxia Yang1, Yu Zhang1, Yan Zhang3, Yunxiao Liu3, Yongqing Shen2,3, Aiying Li1

Corresponding Author:
Yongqing Shen, Aiying Li
Affiliation(s)

1Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China

2Affiliation Key Laboratory for Health Care with Chinese Medicine of Hebei Province, School of Nursing, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China

3College of Nursing, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China

4Department of Clinical Foundation of Chinese Medicine, College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China

Abstract

Tunicamycin (TM), as a natural inhibitor of N-linked glycosylation in eukaryotes, can promote apoptosis and sensitize cancer cells to chemotherapy and radiation therapy in numerous studies. The cardiotoxicity of anticarcinogen always deserved serious consideration. Although the promising anticancer effect of TM is exhilarating, more cardiac adverse reactions are remaining needed to identify and explore. Herein, we focus on the electrophysiological aberration after TM application, and unforeseen found that sinus bradycardia is almost the one and only arrhythmia induced by TM. It implies that the impairment of cardiac pacemaker function should be noticed in the adverse cardiac effect of TM. Furthermore, we found that the TM treatment significantly reduced neonatal cardiomyocytes' automaticity, and diminished. If regulating the cardiac automatic action potential. The current findings illustrate the TM antiarrhythmic mechanism, which might be useful for developing N-glycosylation inhibitor anticarcinogen.

Keywords

Tunicamycin, N-glycosylation, Bradycardia, HCN channel

Cite This Paper

Juanjuan Zhang, Weizhe Liu, Yue Zhang, Hongxia Yang, Yu Zhang, Yan Zhang, Yunxiao Liu, Yongqing Shen, Aiying Li. Tunicamycin Attenuates Cardiac Automaticity by Reducing HCN Current. International Journal of Frontiers in Medicine (2022), Vol. 4, Issue 3: 41-49. https://doi.org/10.25236/IJFM.2022.040307.

References

[1] Tang, L., Chen X., Zhang, X., Guo, Y., Su J., Zhang, J., Peng, C., Chen, X. (2019) N-Glycosylation in progression of skin cancer. Med Oncol, 36:50.

[2] Wu, J., Chen, S., Liu, H., Zhang, Z., Ni, Z., Chen, J., Yang, Z., Nie, Y., Fan, D. (2018) Tunicamycin specifically aggravates ER stress and overcomes chemoresistance in multidrug-resistant gastric cancer cells by inhibiting N-glycosylation. J Exp Clin Cancer Res, 37:272.

[3] Sinevici, N., Mittermayr, S., Davey, G. P., Bones, J., O'Sullivan, J. (2019) Salivary N-glycosylation as a biomarker of oral cancer: A pilot study. Glycobiology,29:726-734.

[4] Mun, D. G., Bhin, J., Kim, S., Kim, H., Jung, J. H., Jung, Y., Jang, Y. E., Park, J. M., Kim, H., Jung, Y., Lee, H., Bae, J., Back, S., Kim, S. J., Kim, J., Park, H., Li, H., Hwang, K. B., Park, Y. S., Yook, J. H., Kim, B. S., Kwon, S. Y., Ryu, S. W., Park, D. Y., Jeon, T. Y., Kim, D. H., Lee, J. H., Han, S. U., Song, K. S., Park, D., Park, J. W., Rodriguez, H., Kim, J., Lee, H., Kim, K. P., Yang, E. G., Kim, H. K., Paek, E., Lee, S., Lee, S. W., Hwang, D. (2019) Proteogenomic Characterization of Human Early-Onset Gastric Cancer. Cancer Cell, 35:111-124.e10.

[5] Vermassen, T., De Bruyne, S., Himpe, J., Lumen, N., Callewaert, N., Rottey, S., Delanghe, J. (2019) N-Linked Glycosylation and Near-Infrared Spectroscopy in the Diagnosis of Prostate Cancer. Int J Mol Sci, 20.

[6] Zhang, J., Ten, Dijke P., Wuhrer, M., Zhang, T. (2021) Role of glycosylation in TGF-β signaling and epithelial-to-mesenchymal transition in cancer. Protein Cell,12:89-106.

[7] Legler, K., Rosprim, R., Karius, T., Eylmann, K., Rossberg, M., Wirtz, R. M., Müller, V., Witzel, I., Schmalfeldt, B., Milde-Langosch, K., Oliveira-Ferrer, L. (2018) Reduced mannosidase MAN1A1 expression leads to aberrant N-glycosylation and impaired survival in breast cancer. Br J Cancer, 118:847-856.

[8] Jones, R. B., Dorsett, K. A., Hjelmeland, A. B., Bellis, S. L. (2018) The ST6Gal-I sialyltransferase protects tumor cells against hypoxia by enhancing HIF-1α signaling. J Biol Chem, 293:5659-5667.

[9] Cui, J., Huang, W., Wu, B., Jin, J., Jing, L., Shi, W. P., Liu, Z. Y., Yuan, L., Luo, D., Li, L., Chen, Z. N., Jiang, J. L. (2018) N-glycosylation by N-acetylglucosaminyltransferase V enhances the interaction of CD147/basigin with integrin β1 and promotes HCC metastasis. J Pathol, 245:41-52.

[10] Pinho, S. S., Reis, C. A. (2015) Glycosylation in cancer: mechanisms and clinical implications. Nat Rev Cancer, 15:540-55.

[11] Surani, M. A. (1979) Glycoprotein synthesis and inhibition of glycosylation by tunicamycin in preimplantation mouse embryos: compaction and trophoblast adhesion. Cell, 18:217-27.

[12] Yoo, J., Mashalidis, E. H., Kuk, A. C. Y., Yamamoto, K., Kaeser, B., Ichikawa, S., Lee S. Y. (2018) GlcNAc-1-P-transferase-tunicamycin complex structure reveals basis for inhibition of N-glycosylation. Nat Struct Mol Biol, 25:217-224.

[13] Hakulinen, J. K., Hering, J., Brändén, G., Chen, H., Snijder, A., Ek, M., Johansson, P. (2017) MraY-antibiotic complex reveals details of tunicamycin mode of action. Nat Chem Biol, 13:265-267.

[14] Sang, X., Li, L., Rui, C., Liu, Y., Liu, Z., Tao, Z., Cheng, H., Liu, P. (2021) Induction of EnR stress by Melatonin enhances the cytotoxic effect of Lapatinib in HER2-positive breast cancer. Cancer Lett, 518:82-93.

[15] Gu, C., Zhang, Y., Chen, D., Liu, H., Mi, K. (2021) Tunicamycin-induced endoplasmic reticulum stress inhibits chemoresistance of FaDu hypopharyngeal carcinoma cells in 3D collagen I cultures and in vivo. Exp Cell Res, 405:112725.

[16] Hou, H., Sun, H., Lu, P., Ge, C., Zhang, L., Li, H., Zhao, F., Tian, H., Zhang, L., Chen, T., Yao, M., Li, J. (2013) Tunicamycin potentiates cisplatin anticancer efficacy through the DPAGT1/Akt/ABCG2 pathway in mouse Xenograft models of human hepatocellular carcinoma. Mol Cancer Ther, 12:2874-84.

[17] Cui, X., Sun, D., Shen, B., Wang, X. (2018) MEG-3-mediated Wnt/β-catenin signaling pathway controls the inhibition of tunicamycin-mediated viability in glioblastoma. Oncol Lett, 16:2797-2804.

[18] Ednie, A. R., Parrish, A. R., Sonner, M. J., Bennett, E. S. (2019) Reduced hybrid/complex N-glycosylation disrupts cardiac electrical signaling and calcium handling in a model of dilated cardiomyopathy. J Mol Cell Cardiol, 132:13-23.

[19] Johnson, D., Montpetit, M. L., Stocker, P. J., Bennett, E. S. (2004) The sialic acid component of the beta1 subunit modulates voltage-gated sodium channel function. J Biol Chem, 279:44303-10.

[20] Marques-da-Silva, D., Francisco, R., Webster, D., Dos Reis Ferreira V., Jaeken, J., Pulinilkunnil, T. (2017) Cardiac complications of congenital disorders of glycosylation (CDG): a systematic review of the literature. J Inherit Metab Dis, 40:657-672.

[21] Kmecova, J., Klimas, J. (2010) Heart rate correction of the QT duration in rats. European journal of pharmacology, 641:187-192.

[22] de-Freitas-Junior, J. C., Bastos, L. G., Freire-Neto, C. A., Rocher, B. D., Abdelhay, E. S., Morgado-Díaz, J. A. (2012) N-glycan biosynthesis inhibitors induce in vitro anticancer activity in colorectal cancer cells. J Cell Biochem, 113:2957-66.

[23] Contessa, J. N., Bhojani, M. S., Freeze, H. H., Rehemtulla, A., Lawrence, T. S. (2008) Inhibition of N-linked glycosylation disrupts receptor tyrosine kinase signaling in tumor cells. Cancer Res, 68:3803-9.

[24] Jung, Y. H., Lim, E. J., Heo, J., Kwon, T. K., Kim, Y. H. (2012) Tunicamycin sensitizes human prostate cells to TRAIL-induced apoptosis by upregulation of TRAIL receptors and downregulation of cIAP2. Int J Oncol, 40:1941-8.

[25] Serrano-Negrón, J. E., Zhang, Z., Rivera-Ruiz, A. P., Banerjee, A., Romero-Nutz, E. C., Sánchez-Torres, N., Baksi, K., Banerjee, D. K. (2018) Tunicamycin-induced ER stress in breast cancer cells neither expresses GRP78 on the surface nor secretes it into the media. Glycobiology, 28:61-68.

[26] Campia, U., Moslehi, J. J., Amiri-Kordestani, L., Barac, A., Beckman, J. A., Chism, D. D., Cohen, P., Groarke, J. D., Herrmann, J., Reilly, C. M., Weintraub, N. L. (2019) Cardio-Oncology: Vascular and Metabolic Perspectives: A Scientific Statement From the American Heart Association. Circulation, 139:e579-e602.

[27] Abdullahi, A., Stanojcic, M., Parousis, A., Patsouris, D., Jeschke, M. G. (2017) Modeling Acute ER Stress in Vivo and in Vitro. Shock, 47:506-513.

[28] Gong, Q., Anderson, C. L., January, C. T., Zhou, Z. (2002) Role of glycosylation in cell surface expression and stability of HERG potassium channels. Am J Physiol Heart Circ Physiol, 283:H77-84.

[29] Watanabe, I., Zhu, J., Recio-Pinto, E., Thornhill, W. B. (2015) The degree of N-glycosylation affects the trafficking and cell surface expression levels of Kv1.4 potassium channels. J Membr Biol, 248:187-96.

[30] Baruscotti, M., Barbuti, A., Bucchi, A. (2010) The cardiac pacemaker current. J Mol Cell Cardiol, 48:55-64.

[31] Baruscotti, M., Bucchi, A., Viscomi, C., Mandelli, G., Consalez, G., Gnecchi-Rusconi, T., Montano, N., Casali, K. R., Micheloni, S., Barbuti, A., DiFrancesco, D. (2011) Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4. Proc Natl Acad Sci U S A, 108:1705-10.

[32] Li, M., Tonggu, L., Tang, L., Wang, L. (2015) Effects of N-glycosylation on hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Biochem J, 466:77-84.

[33] Hegle, A. P., Nazzari, H., Roth, A., Angoli, D., Accili, E. A. (2010) Evolutionary emergence of N-glycosylation as a variable promoter of HCN channel surface expression. Am J Physiol Cell Physiol, 298:C1066-76.