Therapeutic potential of targeting S100A11 in malignant pleural mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor with an unfavorable prognosis. The standard therapeutic approaches are limited to surgery, chemotherapy, and radiotherapy. Because the consequent clinical outcome is often unsatisfactory, a different approach in MPM treatment is required. S100A11, a Ca2+-binding small protein with two EF-hands, is frequently upregulated in various human cancers. Interestingly, it has been found that intracellular and extracellular S100A11 have different functions in cell viability. In this study, we focused on the impact of extracellular S100A11 in MPM and explored the therapeutic potential of an S100A11-targeting strategy. We examined the secretion level of S100A11 in various kinds of cell lines by enzyme-linked immunosorbent assay. Among them, six out of seven MPM cell lines actively secreted S100A11, whereas normal mesothelial cell lines did not secrete it. To investigate the role of secreted S100A11 in MPM, we inhibited its function by neutralizing S100A11 with an anti-S100A11 antibody. Interestingly, the antibody significantly inhibited the proliferation of S100A11-secreting MPM cells in vitro and in vivo. Microarray analysis revealed that several pathways including genes involved in cell proliferation were negatively enriched in the antibody-treated cell lines. In addition, we examined the secretion level of S100A11 in various types of pleural effusions. We found that the secretion of S100A11 was significantly higher in MPM pleural effusions, compared to others, suggesting the possibility for the use of S100A11 as a biomarker. In conclusion, our results indicate that extracellular S100A11 plays important roles in MPM and may be a therapeutic target in S100A11-secreting MPM.

Cancer-cell derived S100A11 promotes macrophage recruitment in ER+ breast cancer

“…Consistent with our findings in ER+ breast cancer cells, previous studies have shown that S100A11 is heterogeneously expressed in solid tumors [31,32]. Overexpression of S100A11 in cervical cancer cells increases their proliferative and migratory abilities [23].…”

Dual effects of targeting S100A11 on suppressing cellular metastatic properties and sensitizing drug response in gastric cancer

“…The dysregulation of S100A11 is linked with oncogenic activities including cancer progression. It has been observed to be overexpressed in many human solid tumours, such as pancreatic, melanoma, breast, ovarian and colorectal cancer [30][31][32][33][34]. Here we propose S100A11 may play a positive role during the development and progression of GC.…”

Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies

“…Over the last 3 years, additional insights into the multiple implications of this protein in the EMT process have been provided, such as its interaction with annexin A2 (Tu et al, 2019), its contribution to higher stiffnessinduced mesenchymal shifts through its membrane translocation (Dong et al, 2019), and its participation in multiple signaling pathways, including MAPK3 (ERK1), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), HGF/ MET, cyclic adenosine monophosphate response element binding protein (CREBBP) and MMP9 (Cui et al, 2021). Finally, the decrease in S100A11 abundance produced by curcumin treatment in our studies in vivo may open up interesting prospects as the only previous published works on this protein in MM reported active secretion of S100A11 by mesothelioma cells in vitro (Saho et al, 2016), while its neutralization by an anti-S100A11 antibody inhibited the proliferation of pleural MM cells in vitro and in vivo (Sato et al, 2018).…”