Biology subjects

Al-Ali, R.

Publications and source records attributed to Al-Ali, R..

3 recordsLinked to original sources

bioRxiv2023

Expression and DNA methylation of 20S proteasome subunits as prognostic and resistance markers in cancer

Proteasomes are involved in the maintenance of cellular protein homeostasis and the control of numerous cellular pathways. Single proteasome genes or subunits have been identified as important players in cancer development and progression without considering the proteasome as a multi-subunit protease. We here conduct a comprehensive pan-cancer analysis encompassing transcriptional, epigenetic, mutational landscapes, pathway enrichments, and survival outcomes linked to the 20S proteasome core complex. The impact of proteasome gene expression on patient survival exhibits a cancer-type dependent pattern. Escalated proteasome expression associates with elevated activation of oncogenic pathways, such as DNA repair, MYC- controlled gene networks, MTORC1 signaling, oxidative phosphorylation, as well as metabolic pathways including glycolysis and fatty acid metabolism. Vice versa, potential loss of function variants correlates with improved survival. The TCGA-derived outcomes are further supported by gene expression analysis of THP-1 cells. Our study reframes these subunits as an integrated functional ensemble, rather than separated subunits. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=179 SRC="FIGDIR/small/571247v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1e50af0org.highwire.dtl.DTLVardef@31521borg.highwire.dtl.DTLVardef@5a949org.highwire.dtl.DTLVardef@1ad1668_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2021

TRIM67 drives tumorigenesis in oligodendrogliomas through Rho GTPase-dependent membrane blebbing

Oligodendrogliomas are a subtype of isocitrate dehydrogenase (IDH) mutant gliomas defined by the co-deletion of chromosome arms 1p and 19q. Although the somatic genomic alterations of oligodendrogliomas have been well described, transcriptional changes unique to these tumors are not well studied. Here, we identify Tripartite Motif Containing 67 (TRIM67), an E3 ubiquitin ligase with essential roles during neuronal development, as an oncogene distinctly upregulated in oligodendrogliomas. We characterize the function of TRIM67 using high throughput assays, including RNA sequencing, total lysate-mass spectrometry (MS) and co-immunoprecipitation (IP)-MS using human neural progenitor cells and patient-derived glioma tumorspheres constitutively overexpressing TRIM67. Our high throughput data suggest that TRIM67 overexpression alters the abundance of cytoskeletal proteins, which were validated by functional assays, including immunofluorescence (IF) staining, co-IP and western blotting (WB). Additionally, IF staining results indicate that TRIM67 ectopic expression induces formation of membrane blebs in glioma cells, which could be reverted with the nonmuscle class II myosin inhibitor blebbistatin and selective ROCK inhibitor fasudil. GTP pulldown and WB assays further indicate that Rho GTPase/ROCK2 signaling is altered upon TRIM67 ectopic expression. Phenotypically, TRIM67 expression resulted in higher cell motility in wound healing experiments, reduced cell adherence in adhesion assays, accelerated tumor growth and reduced survival in mouse orthotopic implantation models of an oligodendroglioma-derived patient tumorsphere line. Taken together, our results demonstrate that upregulated TRIM67 induces blebbing-based rounded cell morphology through Rho GTPase/ROCK-mediated signaling thereby contributing to glioma pathogenesis. SignificanceWe identify TRIM67 as a novel oncogene in oligodendroglioma that leads to increased cell motility, tumor growth, reduced adhesion, and survival in mice. Our results also show that constitutive TRIM67 expression transforms cell morphology from an adherent to a rounded appearance with membrane blebs. Mechanistic alteration of actin cytoskeleton and Rho GTPase signaling upon TRIM67 upregulation underlies the rounded cell structure and the membrane blebbing phenotype. TRIM67-induced blebbing is specifically regulated by RHOA-RAC1-ROCK2 signaling axis. TRIM67 overexpression also alters pathways associated with cell migration and wound healing in various glioma cell lines and human neural progenitor cells, suggesting a general oncogenic mechanism in gliomas. Overall, our study highlights TRIM67 as a novel player orchestrating cytoskeleton, Rho GTPase signaling and bleb-based cell movement, ultimately causing tumorigenic outcomes in oligodendrogliomas.

cancer biology↗

bioRxiv2017

High concentrations of boric acid induce autophagy in cancer cell lines

Background/AimBoric acid (BA) is thought to have anticancer effects, but only a handful of studies tackled this subject. Though a very common compound, little is known about its therapeutic value, mechanisms and effective doses. This study investigates into its therapeutic value and autophagy as a possible mechanism.\n\nMaterials and MethodsWe evaluated the potency of BA treatment in seven different cell lines. We hypothesized that autophagy is involved in the mechanism of BA toxicity in tumor cells based on observations in plants, insects and cancer cell lines. Changes in autophagy-related proteins were measured after BA treatment. Finally, we suspected that blockage of autophagy would increase the effectiveness of BA treatment and enable the use of smaller doses.\n\nResultsOur results demonstrate that all studied cell lines did not suffer mortality in low to medium doses of BA (up to 5mM). However, a high dose (over 25mM) could inflict significant death in all cell lines. Those high doses caused P62/SQSTM1 consumption and LC3II-B accumulation after 3 days of treatment. Using small doses of BA in combination with autophagy blockage did not improve cytotoxicity in lung cancer cell lines.\n\nConclusionWe conclude that high concentrations of BA affect autophagy in short-term treatments. Not enough data is available about BA toxicity, so BA use as cancer treatment can be possible if new toxicity studies are performed.

cancer biology↗