ZIP10 drives osteosarcoma proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway

J Exp Clin Cancer Res. 2021 Oct 27;40(1):340. doi: 10.1186/s13046-021-02146-8.

Abstract

Background: The zinc transporters Zrt- and Irt-related protein (ZIP/SLC39) are overexpressed in human tumors and correlate with poor prognosis; however, their contributions to carcinogenesis and chemoresistance in osteosarcoma (OS) remain unclear.

Methods: We collected 64 OS patient tissues with (n = 12) or without (n = 52) chemotherapy. The expression levels of ZIP10 were measured by immunohistochemistry and applied to prognostic analysis. ZIP10 was knocked down or overexpressed in OS cell lines to explore its effect on proliferation and chemoresistance. RNA sequencing, quantitative real-time PCR, and western blotting analysis were performed to explore ZIP10-regulated downstream target genes. A xenograft mouse model was established to evaluate the mechanisms by which ZIP10 modulates chemoresistance in OS cells.

Results: The expression of ZIP10 was significantly induced by chemotherapy and highly associated with the clinical outcomes of OS. Knockdown of ZIP10 suppressed OS cell proliferation and chemoresistance. In addition, ZIP10 promoted Zn content-induced cAMP-response element binding protein (CREB) phosphorylation and activation, which are required for integrin α10 (ITGA10) transcription and ITGA10-mediated PI3K/AKT pathway activation. Importantly, ITGA10 stimulated PI3K/AKT signaling but not the classical FAK or SRC pathway. Moreover, overexpression of ZIP10 promoted ITGA10 expression and conferred chemoresistance. Treatment with the CREB inhibitor 666-15 or the PI3K/AKT inhibitor GSK690693 impaired tumor chemoresistance in ZIP10-overexpressing cells. Finally, a xenograft mouse model established by subcutaneous injection of 143B cells confirmed that ZIP10 mediates chemotherapy resistance in OS cells via the ZIP10-ITGA10-PI3K/AKT axis.

Conclusions: We demonstrate that ZIP10 drives OS proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway, which might serve as a target for OS treatment.

Keywords: Chemoresistance; ITGA10; Osteosarcoma; PI3K/AKT pathway; ZIP10/SLC39A10.

MeSH terms

  • Animals
  • Cation Transport Proteins / genetics*
  • Cation Transport Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Gene Knockdown Techniques
  • Heterografts
  • Humans
  • Integrin alpha Chains / metabolism*
  • Mice
  • Models, Biological
  • Osteosarcoma / genetics*
  • Osteosarcoma / metabolism*
  • Osteosarcoma / pathology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction*

Substances

  • Cation Transport Proteins
  • Cyclic AMP Response Element-Binding Protein
  • Integrin alpha Chains
  • SLC39A10 protein, human
  • integrin alpha 10
  • Proto-Oncogene Proteins c-akt