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Chosdol, K.

Publications and source records attributed to Chosdol, K..

4 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

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↗
bioRxiv2023

The atypical cadherin FAT1 is a novel regulator of STAT1, driving its pro-tumorigenic effect via the STAT1/PDCD4 axis in glioblastoma

FAT1 is an atypical cadherin that has been shown to act both as an oncogene and a tumour suppressor gene (TSG) in different tumor types. We have earlier shown that upregulated FAT1 acts as an oncogene in glial tumors by promoting pro-tumorigenic inflammation and EMT in primary human glioblastoma and in cell lines. One effect was through the suppression of the Tumor Suppressor Gene (TSG), Programmed Cell Death 4 (PDCD4). Here, we have studied how, in glioblastoma, upregulated FAT1 affects downstream events that control PDCD4 expression. In silico analysis of the PDCD4 promoter revealed multiple STAT1 binding sites. We also found a positive correlation in mRNA levels of STAT1 and FAT1 in the Glioblastoma databases, as well as in resected patient derived tumor samples by qPCR. Increased FAT1 as well as STAT1 were associated with poor prognosis in these data bases. In the glioblastoma cell lines LN229 and U87MG, FAT1 knockdown resulted in decreased STAT1 expression. Also, STAT1 knockdown resulted in increased PDCD4 expression, implying that STAT1 may mediate FAT1s role in suppressing PDCD4. Further, ChIP experiments showed that STAT1 protein binds to the PDCD4 promoter and upon FAT1 knockdown, STAT1 binding to the PDCD4 promoter reduces. As for FAT1, STAT1 knockdown also reduces the expression of pro-inflammatory cytokines and EMT markers, also migration and invasion of glioma derived cell lines. This work identifies STAT1 as a novel downstream mediator of FAT1 which mediates its pro-tumorigenic action in suppressing the TSG, PDCD4.

cancer biology↗