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Coinhibition of S1pr1 and Gp130 by Sirna-Loaded Alginate-Conjugated Trimethyl Chitosan Nanoparticles Robustly Blocks Development of Cancer Cells Publisher Pubmed



Rostami N1, 2 ; Nikkhoo A1 ; Khazaeipoul Y3 ; Farhadi S3 ; Sadat Haeri M1 ; Moghadaszadeh Ardebili S5 ; Aghaei Vanda N1 ; Atyabi F4 ; Namdar A6 ; Baghaei M4 ; Haghnavaz N1 ; Kazemi T1 ; Yousefi M7 ; Ghalamfarsa G8 Show All Authors
Authors
  1. Rostami N1, 2
  2. Nikkhoo A1
  3. Khazaeipoul Y3
  4. Farhadi S3
  5. Sadat Haeri M1
  6. Moghadaszadeh Ardebili S5
  7. Aghaei Vanda N1
  8. Atyabi F4
  9. Namdar A6
  10. Baghaei M4
  11. Haghnavaz N1
  12. Kazemi T1
  13. Yousefi M7
  14. Ghalamfarsa G8
  15. Sabz G8
  16. Jadidiniaragh F1, 9
Show Affiliations
Authors Affiliations
  1. 1. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  2. 2. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
  3. 3. Student Research Committee, Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  4. 4. Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  6. 6. Department of Oncology, Cross Cancer Institute, The University of Alberta, Edmonton, AB, Canada
  7. 7. Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  8. 8. Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
  9. 9. Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

Source: Journal of Cellular Physiology Published:2020


Abstract

There is an interconnected network between S1P/sphingosine-1-phosphate receptor 1 (S1PR1), IL-6/glycoprotein 130 (GP130), and signal transducer and activator of transcription 3 (STAT3) signaling pathways in the tumor microenvironment, which leads to cancer progression. S1P/S1PR1 and IL-6/GP130 signaling pathways phosphorylate and activate STAT3, and it then induces the expression of S1PR1 and interleukin-6 (IL-6) in a positive feedback loop leading to cancer progression. We hypothesized that blockade of this amplification loop can suppress the growth and development of cancer cells. Therefore, we silenced STAT3 upstream molecules including the S1PR1 and GP130 molecules in cancer cells using small interfering RNA (siRNA)-loaded alginate-conjugated trimethyl chitosan (ATMC) nanoparticles (NPs). The generated NPs had competent properties including the appropriate size, zeta potential, polydispersity index, morphology, high uptake of siRNA, high rate of capacity, high stability, and low toxicity. We evaluated the effects of siRNA loaded ATMC NPs on tumor hallmarks of three murine-derived cancer cell lines, including 4T1 (breast cancer), B16-F10 (melanoma), and CT26 (colon cancer). The results confirmed the tumor-suppressive effects of combinational targeting of S1PR1 and GP130. Moreover, combination therapy could potently suppress tumor growth as assessed by the chick chorioallantoic membrane assay. In this study, we targeted this positive feedback loop for the first time and applied this novel combination therapy, which provides a promising approach for cancer treatment. The development of a potent nanocarrier system with ATMC for this combination was also another aspect of this study, which should be further investigated in cancer animal models in further studies. © 2020 Wiley Periodicals LLC
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