Abstract
The role of autophagy in the development and progression of hepatocellular carcinoma (HCC) is ambiguous and still little known. Autophagy stimulation may be of exceptional interest in antitumor pharmacotherapy of HCC. Rapamycin and lithium are typical inducers of autophagy. The aim of this study was to compare the level of autophagy in hepatocellular carcinoma-29 (HCC-29) cells after single and combined administration of lithium carbonate and rapamycin. Autolysosomes formation and significant increase of LC3 beta (+)– and LAMP1 (+)– autophagic structures were revealed in HCC-29 cells after lithium carbonate and rapamycin coadministration by transmission electron microscopy and immunofluorescence analysis. Using this combination of drugs may be a promising strategy for HCC chemotherapy, since it will allow the integration of various cellular signaling pathways that regulate autophagy and apoptosis in tumor cells.
Similar content being viewed by others
REFERENCES
Ávalos, Y., Canales, J., Bravo-Sagua, R., Criollo, A., Lavandero, S., and Quest, A.F., Tumor suppression and promotion by autophagy, Biomed. Res. Int., 2014, p. 603980. https://doi.org/10.1155/2014/603980
Bento, C.F., Renna, M., Ghislat, G., Puri, C., Ashkenazi, A., Vicinanza, M., Menzies, F.M., and Rubinsztein, D.C., Mammalian autophagy: how does it work?, Annu. Rev. Biochem., 2016, vol. 85, pp. 685–713.
Bgatova, N.P., Gavrilova, Yu.S., Lykov, A.P., Solovieva, A.O., Makarova, V.V., Borodin, Yu.I., and Konenkov, V.I., Apoptosis and autophagy in hepatocarcinoma cells induced by different forms of lithium salts, Cell Tissue Biol., 2017, vol. 11, no. 4, pp. 261–267.
Cuervo, A.M. and Wong, E., Chaperone-mediated autophagy: roles in disease and aging, Cell Res., 2014, vol. 1, pp. 92–104.
Dash, S., Chava, S., Chandra, P.K., Aydin, Y., Balart, L.A., and Wu, T., Autophagy in hepatocellular carcinomas: from pathophysiology to therapeutic response, Hepat. Med., 2016, vol. 8, pp. 9–20.
DeYoung, M.P., Horak, P., Sofer, A., Sgroi, D., and Ellisen, L.W., Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling, Genes. Dev., 2008, vol. 2, pp. 239–251.
Gavrilova, Y.S., Bgatova, N.P., Solov’eva, A.O., Trifonova, K.E., Lykov, A.P., Borodin, Y.I., and Konenkov, V.I., Target cells for lithium in different forms within a heterogeneous hepatocarcinoma-29 population, Cell Tissue Biol., 2016, vol. 10, no. 4, pp. 284–289.
Germano, D. and Daniele, B., Systemic therapy of hepatocellular carcinoma: current status and future perspectives, World J. Gastroenterol., 2014, vol. 12, pp. 3087–3099.
Huang, J. and Manning, B.D., The TSC1-TSC2 complex: a molecular switchboard controlling cell growth, Biochem. J., 2008, vol. 2, pp. 179–190.
Inoki, K., Zhu, T., and Guan, K.L., TSC2 mediates cellular energy response to control cell growth and survival, Cell, 2003a, vol. 5, pp. 577–590.
Inoki, K., Li, Y., Xu, T., and Guan, K.L., Rheb GTPase is a direct target of TSC2 GAP activity and regulates MTOR signaling, Genes Dev., 2003b, vol. 15, pp. 1829–1834.
Inoki, K., Ouyang, H., Zhu, T., Lindvall, C., Wang, Y., Zhang, X., Yang, Q., Bennett, C., Harada, Y., Stankunas, K., Wang, C.Y., He, X., MacDougald, O.A., You, M., Williams, B.O., and Guan, K.L., TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth, Cell, 2006, vol. 126, pp. 955–968.
Kaledin, V.I., Zhukova, N.A., Nikolin, V.P. Popova, N.A., Belyaev, M.D., Baginskaya, N.V., Litvinova, E.A., Tolstikova, T.G., Lushnikova, E.L., and Semenov, D.E., Hepatocellular carcinoma-29—metastatic transplantable tumor of mice causing cachexia, Bull. Exp. Biol. Med., 2009, vol. 148, no. 12, pp. 664–669.
Li, Y.Y., Feun, L.G., Thongkum, A., Tu, C.H., Chen, S.M., Wangpaichitr, M., Wu, C., Kuo, M.T., and Savaraj, N., Autophagic mechanism in anti-cancer immunity: its pros and cons for cancer therapy, Int. J. Mol. Sci., 2017, vol. 18. https://doi.org/10.3390/ijms18061297
Liu, L., Liao, J.Z., He, X.X., and Li, P.Y., The role of autophagy in hepatocellular carcinoma: friend or foe, Oncotarget, 2017, vol. 34, pp. 57 707–57 722.
Manning, B.D., Tee, A.R., Logsdon, M.N., Blenis, J., and Cantley, L.C., Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway, Mol. Cell, 2002, vol. 1, pp. 151–62.
Noda, T. and Ohsumi, Y., TOR, a phosphatidylinositol kinase homologue, controls autophagy in yeast, J. Biol. Chem., 1998, vol. 273, pp. 3963–3966.
Parzych, K.R. and Klionsky, D.J., An overview of autophagy: morphology, mechanism, and regulation, Antioxid. Redox. Signal., 2014, vol. 3, pp. 460–473.
Quiroz, J.A., Gould, T.D., Manji, and H.K., Molecular Effects of lithium, J. Mol. Interv., 2004, vol. 5, pp. 259–272.
Russo, M. and Russo, G.L., Autophagy inducers in cancer, Biochem. Pharmacol., 2018, vol. 153, pp. 51–61.
Sade, Y., Toker, L., Kara, N.Z., Einat, H., Rapoport, S., Moechars, D., Berry, G.T., Bersudsky, Y., and Agam, G., IP3 accumulation and/or inositol depletion: two downstream lithium’s effects that may mediate its behavioral and cellular changes, Transl. Psychiatry, 2016, vol. 6. e968. https://doi.org/10.1038/tp.2016.217
Sarkar, S., Floto, R.A., Berger, Z., Imarisio, S., Cordenier, A., Pasco, M., Cook, L.J., and Rubinsztein, D.C., Lithium induces autophagy by inhibiting inositol monophosphatase, J. Cell Biol., 2005, vol. 170, pp. 1101–1111.
Sarkar, S., Krishna, G., Imarisio, S., Saiki, S., O’Kane, C.J., and Rubinsztein, D.C., A rational mechanism for combination treatment of huntington’s disease using lithium and rapamycin, Hum. Mol. Genet., 2008, vol. 2, pp. 170–178.
Sarkar, S., Ravikumar, B., Floto, R.A., and Rubinsztein, D.C., Rapamycin and MTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies, Cell Death Differ., 2009, vol. 1, pp. 46–56.
Sato, T., Nakashima, A., Guo, L., Coffman, K., and Tamanoi, F., Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer, Oncogene, 2010, vol. 18, pp. 2746–2752.
Shoshani, T.Faerman, A., Mett, I., Zelin, E., Tenne, T., Gorodin, S., Moshel, Y., Elbaz, S., Budanov, A., Chajut, A., Kalinski, H., Kamer, I., Rozen, A., Mor, O., Keshet, E., Leshkowitz, D., Einat, P., Skaliter, R., and Feinstein, E., Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis, Mol. Cell Biol., 2002, vol. 7, pp. 2283–2293.
Song, M.J. and Bae, S.H., Newer treatments for advanced hepatocellular carcinoma, Korean J. Intern. Med., 2014, vol. 2, pp. 149–155.
Taskaeva, Iu. and Bgatova, N., Ultrastructural and immunofluorescent analysis of lithium effects on autophagy in hepatocellular carcinoma cells, Asian Pac. J. Cancer Biol., 2018, vol. 3, pp. 83–87.
Taskaeva, Iu.S. and Bgatova, N.P., Ultrastructural changes in hepatocellular carcinoma-29 cells with lithium carbonate introduction in vivo, Bull. Exp. Biol. Med., 2019, vol. 167, no. 1, pp. 94–98.
Vicencio, J.M., Ortiz, C., Criollo, A., Jones, A.W., Kepp, O., Galluzzi, L., Joza, N., Vitale, I., Morselli, E., Tailler, M., Castedo, M., Maiuri, M.C., Molgó, J., Szabadkai, G., Lavandero, S., and Kroemer, G., The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with beclin 1, Cell Death Differ., 2009, vol. 16, pp. 1006–1017.
Yang, Z. and Klionsky, D.J., An overview of the molecular mechanism of autophagy, Curr. Top. Microbiol. Immunol., 2009, vol. 335, pp. 1–32.
Yin, Z., Pascual, C., and Klionsky, D.J., Autophagy: machinery and regulation, Microb. Cell., 2016, vol. 12, pp. 588–596.
Zhi, X. and Zhong, Q., Autophagy in cancer, F1000Prime Rep., 2015, vol. 7, p. 18. https://doi.org/10.12703/P7-18
Funding
This work was supported with financing of the Novosibirsk Scientific-Research Institute of Clinical and Experimental Lymphology as part of a state order, no. 0324-2019-0045.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
COMPLIANCE WITH ETHICAL STANDARDS
The authors declare that they have no conflict of interest. This article does not contain any studies involving animals or human participants performed by any of the authors.
AUTHOR CONTRIBUTIONS
The concept and design of the study, as well as the analysis and interpretation of the data, were carried out by Iu.S. Taskaeva and N.P. Bgatova, collection and processing of material were done by Iu.S. Taskaeva and A.O. Solovieva, and statistical data processing and paper writing were done by Iu.S. Taskaeva.
Additional information
Translated by I. Fridlyanskaya
Abbreviations: HCC—hepatocellular carcinoma, HCC-29—hepatocellular carcinoma-29, AKT—protein kinase B, GSK-3β—glycogen synthase kinase-3β, IMPase—inosytol monophosphatase, IP3—inositol-1,4,5-triphosphate, IP3R–IP3 receptor, mTOR—mammalian target for rapamycin, PI3K—phosphatidylinositol 3-kinase, TSC 1/2—tuberous sclerosis complex 1/2.
Rights and permissions
About this article
Cite this article
Taskaeva, I.S., Bgatova, N.P. & Solovieva, A.O. Autophagy in Hepatocellular Carcinoma-29 after Single or Combined Administration of Lithium Carbonate and Rapamycin. Cell Tiss. Biol. 13, 353–359 (2019). https://doi.org/10.1134/S1990519X19050079
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S1990519X19050079