Abstract 699: Inhibition of cathepsin L1 by U87 KIF9 suppression in glioblastoma multiforme: a potential therapeutic target

Abstract

Abstract Glioblastoma multiforme is a fatal primary brain cancer. It has remained one of the most difficult cancers to treat because of glioblastomas’ aggressive and local invasive nature. Glioblastoma tumors have many myeloid cells, especially microglia. Increased levels of microglia result in increased glioblastoma invasion and are associated with worse clinical outcomes. Glioblastomas’ infiltrative mechanisms are mostly unknown which hinder the efficacy of current treatments. Therefore, further investigations on the mechanisms responsible for local invasion are potential targets for therapeutic interventions. Recently, there has been interest in evaluating the role of kinesin family members (KIFs) and cathepsins (CTS) as possible targets for therapeutic interventions. KIFs play an essential role in both physiological axonal transport processes and in processes of cell division. Previous studies have investigated the inhibition of KIF11 as a possible therapeutic target in glioblastoma. Preliminary studies in our group have found that the inhibition of KIF9 reduces microglia-stimulated glioma invasion. CTS, which are proteases that function in many pathways and increase neoplastic progression, are other possible therapeutic targets. Specifically in glioblastoma, inhibition of cathepsin L1 (CTSL1) (i) promotes tumor cell death, (ii) decreases apoptosis threshold and (iii) sensitizes glioblastoma cells to radiation. Our study investigated the role of KIF9 suppression in secretion and production of CTSL1. In order to investigate this relationship, U87 cells were incubated with and without the presence of microglia. Non-targeting and stable KIF9 knockdown cells were incubated with and without the presence of microglia. CTSL1 concentration levels were measured by enzyme immunoassay (ELISA). We investigated CTSL1 concentrations in the cell lysates as well as the cell supernatants. Our results demonstrated an overall decrease in production and secretion of CTSL1 in KIF9 knockdown cells as compared to non-targeting shRNA cells. The effect of KIF9 knockdown was evident in the presence and absence of microglia. Although the exact mechanism needs to be further clarified, inhibition of CTSL1 by KIF9 suppression could be a possible potential target for therapeutic intervention. Citation Format: Maria M. Rubinstein, Jeffrey Segall. Inhibition of cathepsin L1 by U87 KIF9 suppression in glioblastoma multiforme: a potential therapeutic target. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 699.