Biology subjects

Bissa, B.

Publications and source records attributed to Bissa, B..

3 recordsLinked to original sources

bioRxiv2025

DRP1-mediated mitochondrial dynamics orchestrate EMT in glioblastoma cells

BackgroundEpithelial to mesenchymal transition (EMT), a differentiation process, frequently imparts invasive properties in Glioblastoma Multiforme (GBM), which leads to a poor prognosis. Cells lose apical-basal polarity, cell-cell connections, and/or chemo-resistance during EMT, which can result in the spread of cancer and the acquisition of additional stem cell-like traits. It is unclear how organelle dynamics influence EMT in this respect. The interaction between cytoskeletal and mitochondrial regulators governing GBM cell EMT is explored in this article. Results and DiscussionIn GBM cells, we observed that TGF-{beta}-induced EMT led to a proliferative arrest, which was accompanied by a fragmented mitochondrial morphology, elevated expression of fission markers such as DRP1, MFF, and FIS1, and most importantly, localization of mitochondria near the cell boundaries. An increase in mitochondrial ROS accompanied this, but their functional status was indicated by a higher oxygen consumption rate (OCR). Additionally, cytoskeleton re-distribution and EMT reversal were the outcomes of si-RNA-mediated elimination of the fission-marker DRP-1 or pharmacological inhibition of fission by Mdivi-1. On the other hand, drugs that disrupt the cytoskeleton, shifted the spatial distribution of mitochondria to the perinuclear area, which had an adverse effect on EMT. Notably, it was shown that RhoA, a protein that helps organize the actin cytoskeleton, co-immunoprecipitates with DRP1 and governs both cytoskeletal dynamics and mitochondrial fission in its presence. ConclusionOur research sheds substantial insight on the current interactions between the cytoskeleton and mitochondrial spatial dynamics that control EMT in GBM cells, which may have significant therapeutic implications. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/694080v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@81b796org.highwire.dtl.DTLVardef@3bec9aorg.highwire.dtl.DTLVardef@2a79c3org.highwire.dtl.DTLVardef@9ff14a_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Reciprocal regulation of autophagy and exosome pathway is mediated by GABARAPL2 and Alix to facilitate cellular homeostasis

The continuous reliance of cancer cells to acquire energy and communicate their nutrient needs makes them resilient and vulnerable. It provides an opportunity to stifle cancer cells by restricting their energy generation and communication ability. Autophagy and exosome biogenesis are two such pathways that are essential in maintaining the robust growth and survival of cancer cells. In this study we observed that inhibition of one pathway altered the expression of genes in other pathway. Exosome biogenesis, when blocked, led to an increase in breast cancer cell proliferation, while inhibition of autophagy did not significantly affect cancer cell proliferation. Therefore, the two pathways, when independently inhibited, did not present any significant effect on restricting cancer cell growth. However, we observed a substantial reduction in cancer cell proliferation upon combined inhibition of two pathways. To evaluate the reciprocal regulation of two pathways, we blocked the autophagy pathway and observed increase in the secretion of exosomes from MDA-MB-231 cells, along with decreased expression of Alix and CD63. On contrary, inhibition of exosome biogenesis led to an increase in the expression of ATG5 and ATG16L1, which caused a significant decrease in expression of GABARAPL2. Interestingly, the knockdown of GABARAPL2 abrogated the decrease in Alix expression upon autophagy inhibition, thus highlighting the essential role of GABARAPL2 in Alix secretion. Thus, our study highlights for the first time the synergistic effects of autophagy and exosome pathway inhibition in restricting cancer cell growth as well as the involvement of GABARAPL2 in the regulation of exosome secretion via modulating Alix expression.

cancer biology↗

bioRxiv2024

Differential expression of GABARAPs in GBM renders temozolomide sensitivity in a p53-dependent manner

Glioblastoma (GBM) is one of the most debilitating and extremely aggressive tumors, with a median survival of less than a year. GBMs have high metastatic potential and frequently acquire chemoresistance. The current multimodal treatment approaches for GBM include surgical tumor resurrection, radiotherapy, and chemotherapy but these approaches leave the patient with long-term disabilities such as depletion of cognitive abilities, leukoencephalopathy, and recurrence in 6-8 months. Glioma cells are highly dependent on autophagy to survive and proliferate. Autophagy inhibition has proven to be a beneficial strategy for restricting glioma growth. However, the autophagy pathway cannot be efficiently targeted due to the lack of specific autophagy inhibitors. Understanding the vulnerabilities in autophagy gene expression can help to design better autophagy inhibitors. This study demonstrates the differential expression of GABARAP family members in low-grade glioma and GBM. Our study highlights the differential expression of GABARAP family members in response to autophagy inhibition and induction. Moreover, the knockdown of specific GABARAP family members enhanced proliferation and reduced temozolomide (TMZ) sensitivity of glial cells by decreasing the p53 expression. The selective expression pattern of GABARAP genes in Glioblastoma can be utilized to screen for patients who might respond better to temozolomide treatment. The differential expression of GABARAP family members highlights the subtle regulation of the autophagy pathway in response to environmental cues.

cancer biology↗