Lysosomes in glioblastoma: pump up the volume

Figures & data

Figure 1. Overview of lysosomal functions.

Lysosomes assemble from both neo-synthetized and endocytosed materials. Their cargos are delivered through the transgolgi network (TGN) or the multivesicular bodies (MVB). MVB themselves emanate from endosomes and/or TGN. Lysosomes exerted varied cellular functions, including: metabolic signaling via mammalian/mechanistic Target Of Rapamycin Complex 1 (mTORC1) docking on their surface, protein turnover via the degradation of cellular contents following fusion with autophagosomes (autophagy) or endosomes, and exocytosis via fusion with the plasma membrane.

Figure 2. Therapeutic targeting of the lysosome.

Numerous pharmacological compounds are reported to alter lysosomal functions and stability. mammalian/mechanistic Target Of Rapamycin (mTOR) inhibitors prevent metabolic signaling from occurring and induce initiation of autophagy. Bafilomycin A1 blocks the lysosomal proton pump (vATPase), elevating pH and therefore limiting catabolic actions. Chloroquine increases lysosomal pH, reducing degradative capacity and fusion with autophagosomes. Lysosomal Membrane Permeabilization (LMP) inducing drugs destabilize the organelle membrane, allowing for the leakage of lysosomal proteases into the cytosol and ultimately resulting in cell death.

Figure 3. MALT1 interacts with QKI and regulates lysosomal homeostasis in Glioblastoma Stem-like Cells.

Mucosa-Associated Lymphoid Tissue lymphoma translocation protein 1 (MALT1) interacts with QKI in Glioblastoma Stem-like Cells (GSCs), thus restraining QKI activity. Upon MALT1 inhibition, QKI is released and possibly free to bind to lysosome-coding mRNAs, leading to lysosomal biogenesis. This lysosomal exaggeration ruptures its integrity, culminating in mTOR (mammalian/mechanistic Target Of Rapamycin Complex 1) dispersion, and lysosomal membrane permeabilization (LMP). As a result, lysosomal proteases induce GSC death, thus restraining GBM development.

Table 1. Compounds reported to induce lysosome membrane permeabilization in glioblastoma.

Chemical Drug (Name)	Family	Structure	Molecular/ Functional Targets	Reference
GDC-0941 (PICTILISIB)	anti-neoplasic		Phosphatidyl Inositol 3 Kinase [PI3 K)	[76]
Lys05	polyamine		Cationic Amphiphilic Drug [CAD]	[77]
Lu-28-179 (SIRAMESINE]	anti-depressant		Cationic Amphiphilic Drug [CAD)	78
SapC-DOPS [BXQ-350]	nanovesicle	n.a	Lysosomal Sphingolipid Metabolism	[81]
TLI	combination	n.a	Lysosomal Sphingolipid Metabolism	[82]
Clemastine (TAVIST]	anti-histamine		Cationic Amphiphilic Drug [CAD)	[8]
Mepazine [PACATAL]	anti-psychotic		MALT1 Paracaspase	[7]
SKI-II	sphingosine kinase-2 inhibitor		Sphingosine Kinase	[82]

This table summarizes reported drugs with poisoning capability on glioblastoma cells in vitro. Chemical and brand names are recapitulated, alongside family of each compound, structure, and reference. TLI: TNFα, Lipopolysaccharide, Interferonγ; n.a: not available.

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