Control of the Endo-Lysosome Homeostasis by the Paracaspase MALT1 regulates Glioma Cell Survival

Abstract

Glioblastoma is one of the most lethal forms of adult cancer with a median survival of around 15 months. A potential treatment strategy involves targeting glioblastoma stem-like cells (GSC), which constitute a cell autonomous reservoir of aberrant cells able to initiate, maintain, and repopulate the tumor mass. Here, we report that the expression of the paracaspase mucosa-associated lymphoid tissue l (MALT1), a protease previously linked to antigen receptor-mediated NF-κB activation and B-cell lymphoma survival, inversely correlates with patient probability of survival. The knockdown of MALT1 largely impaired the expansion of patient-derived stem-like cells in vitro, and this could be recapitulated with pharmacological inhibitors, in vitro and in vivo. Blocking MALT1 protease activity increases the endo-lysosome abundance, impaired autophagic flux, and culminates in lysosomalmediated death, concomitantly with mTOR inactivation and dispersion from lysosomes.These findings place MALT1 as a new druggable target involved in glioblastoma and unveil ways to modulate the homeostasis of endo-lysosomes.

MALT1 Proteolytic Activity Suppresses Autoimmunity in a T Cell Intrinsic Manner

“…This, as well as the signal fine-tuning by an enzymatic activity, makes MALT1 protease activity a very attractive therapeutic target in humans for the treatment of autoimmunity and some cancers. At this moment, several independent studies have described active site or allosteric MALT1 protease inhibitors (11–14, 40–45), and mouse studies have already indicated the therapeutic value of some of these inhibitors in certain types of cancer (13, 14, 43, 46) and inflammatory diseases (40). Recently, four independent papers reported unexpected autoimmune phenotypes such as multi-organ inflammation, including the stomach, and ataxia in full-body Malt1 -PD mice (4–6, 47), which could indicate a risk when inhibiting MALT1 protease activity for therapeutic reasons.…”

In vitro anticancer activity of fluphenazine, perphenazine and prochlorperazine. A review

“…In the case of brain cancer DNA fragmentation of SK‐SY‐5Y cells after FLU and perphenazine treatment (Gil‐Ad et al, 2004), no impact was shown on the cell cycle (G 2 /M and G 0 /G 1 ), caspases, ATP level and pAKT/AKT expression in U87‐MG cells after perphenazine treatment (Tzadok et al, 2010) was observed. In addition, no impact on activation and phosphorylation of AKT, S6 and p70S6K levels after FLU treatment in GSC#9 cells (Jacobs et al, 2019) was reported. On the other hand, in the case of breast cancer, invasion, migration, tumorsphere formation as well as stimulation of apoptosis were observed in MDA‐MB‐231 and Hs578T cells incubated with FLU (Goyette et al, 2019).…”

“…The authors observed a concentration-dependent decrease in viability after a 4-day incubation of the BT478 brain metastasis initiating cell line with prochlorperazine in the concentration range 0-100 μM at EC 50 = 11.9 μM (Singh et al, 2018). Jacobs et al (2019) analyzed the viability of two types of glioblastoma patient-derived mesenchymal (GSC#1) and classical (GSC#9) cells with stem-like properties and observed 95% reduction in viability after 24 hours of exposure to FLU at a concentration of 20 μM. This was possibly due to the MALT1 protease inhibition.…”

“…Jacobs et al (2019) analyzed the viability of two types of glioblastoma patient‐derived mesenchymal (GSC#1) and classical (GSC#9) cells with stem‐like properties and observed 95% reduction in viability after 24 hours of exposure to FLU at a concentration of 20 μ m . This was possibly due to the MALT1 protease inhibition.…”

“…This was possibly due to the MALT1 protease inhibition. Moreover, the analysis of AKT, S6 and p70S6K levels in the lysate of GSC#9 cells after 1 hour of treatment with FLU (20 μ m ) showed that the drug did not affect activation and phosphorylation of the analyzed proteins (Jacobs et al, 2019).…”