Exosomes and development of cancer cell resistance to metformin: pilot study

Objective: to study the role of the intercellular interactions in the progression of the cancer cells resistance to metformin, a biguanide antidiabetic drug exhibited the marked anti-tumor activity.

Results. Earlier we have demonstrated the effect of horizontal transferring of hormonal resistance of breast cancer cells  from cell to cell, and showed the key role of exosomes on the transferring of the resistance. Here we have shown the effect of the horizontal transferring of metformin resistance in breast cancer cells – similar to the progression of hormonal resistance. We found that horizontal transferring of the metformin resistance is mediated via exosomes secreted by the resistant cells. The proteome analysis of the exosomes revealed several proteins differentially expressed in the exosomes of metformin-resistant cells and associated with the regulation of cell response to apoptotic drugs.

Conclusions. Totally, the data presented demonstrate the new mechanism of the development of the cancer cell resistance based on the intercellular interactions, opening the new insights in the target therapy of breast cancer.

1. Evans J.M., Donnelly L.A., Emslie- Smith A.M. et al. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005;330(7503):1304–5.

2. Shcherbakov A.M., Andreeva O.E., Shatskaya V.A., Krasil’nikov M.A. The relationships between snail1 and estrogen receptor signaling in breast cancer cells. J Cell Biochem 2012;113(6):2147–55.

3. Viedma-Rodriguez R., Baiza-Gutman L., Salamanca-Gómez F. et al. Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer (review). Oncol Rep 2014;32(1):3–15.

4. Nalvarte I., Schwend T., Gustafsson J.A. Proteomics analysis of the estrogen receptor alpha receptosome. Mol Cell Proteomics 2010;9(7):1411–22.

5. Bihani T., Ezell S.A., Ladd B. et al. Resistance to everolimus driven by epigenetic regulation of MYC in ER+ breast cancers. Oncotarget 2015;6(4):2407–20.

6. Oliveras-Ferraros C., Vazquez-Martin A., Cuyàs E. et al. Acquired resistance to metformin in breast cancer cells triggers transcriptome reprogramming toward a degradome-related metastatic stem-like profile. Cell Cycle 2014;13(7):1132–44.

7. Shcherbakov A.M., Sorokin D.V., Tatar- skiy V.V. Jr et al. The phenomenon of acquired resistance to metformin in breast cancer cells: the interaction of growth pathways and estrogen receptor signaling. IUBMB Life 2016;68(4):281–92.

8. Семина С.Е., Багров Д.В., Красильников М.А. Межклеточные взаимодействия и развитие гормональной резистентности клеток рака молочной железы. Успехи молекулярной онкологии 2015;2(2):50–5. [Semina S.E., Bagrov D.V., Krasil’nikov M.A. Intercellular interactions and progression of hormonal resistance of breast cancer cells. Uspekhi molekulyarnoy onkologii = Advances in Molecular Oncology 2015;2(2):50–5. (In Russ.)].

9. Reid G., Hübner M.R., Métivier R. et al. Cyclic, proteasome-mediated turnover of unliganded and liganded ERalpha on responsive promoters is an integral feature of estrogen signaling. Mol Cell 2003;11(3):695–707.

10. Thery C., Amigorena S., Raposo G., Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol 2006. Chapter 3: Unit 3.22.

11. Yang B., Wang S., Yu S. et al. C1q/tumor necrosis factor-related protein 3 inhibits oxidative stress during intracerebral hemorrhage via PKA signaling. Brain Res 2017;1657:176–84.

12. Choi J., Kim D.I., Kim J. et al. Hornerin is involved in breast cancer progression. J Breast Cancer 2016;19(2): 142–7.

13. Wang Z.C., E D., Batu D.L. et al. 2DDIGE proteomic analysis of changes in estrogen/progesterone-induced rat breast hyperplasia upon treatment with the Mongolian remedy RuXian-I. Molecules 2011;16(4):3048–65.

14. Queiroz E.A., Puukila S., Eichler R. et al. Metformin induces apoptosis and cell cycle arrest mediated by oxidative stress, AMPK and FOXO3a in MCF-7 breast cancer cells. PLoS One 2014;9(5): e98207