Biology subjects

Kochetkova, E.

Publications and source records attributed to Kochetkova, E..

4 recordsLinked to original sources

bioRxiv2026

Oncogenic ERK signaling represses chaperone-mediated autophagy through transcriptional control of LAMP-2A

Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway governed by the rate-limiting receptor LAMP-2A and increasingly implicated in cancer. However, the oncogenic circuits that enforce CMA repression and whether this state is therapeutically reversible remain unclear. Here, we developed a quantitative bioluminescence-based reporter to measure CMA activity in human cancer cells and combined parallel chemical and genome-scale CRISPR-Cas9 screens to define regulatory pathways. The chemical screen identified GSK1059615 as a CMA-restoring compound that increased LAMP-2A transcription and protein abundance in vitro and in vivo. In parallel, the CRISPR screen revealed ERK signaling as a pathway-level suppressor of CMA. Genetic or pharmacologic ERK inhibition de-repressed LAMP-2A expression, while integrated modulation of ERK, PI3K-AKT, and p38 signaling coordinated transcriptional induction and stabilization of LAMP-2A. Transcriptomic analyses further implicated FOXO1/FOXP1-driven programs in LAMP-2A regulation. Together, these findings position CMA as an integrated output of oncogenic signaling networks and establish a mechanistic framework for restoring CMA activity in defined cancer contexts.

cell biology↗

bioRxiv2025

Novelty, category and orientation tuning for printed characters: a magnetoencephalography study with fast periodic visual stimulation

Letter recognition is assumed to involve several levels of analysis, including coarse tuning for category and novelty and more fine tuning, related to letter orientation. We employed an oddball fast periodic visual stimulation (FPVS) paradigm with magnetoencephalography (Elekta VectorView, 306 sensors) to study neural discrimination responses in the source space. Using contrasts between native letters and foreign letters, digits, or inverted native letters, we aimed to isolate the neural responses to visual novelty, category, and orientation during character analysis. The study was conducted with a cohort of 25 adults. The response topography demonstrated bilateral organization, including language-related brain regions as ventral occipitotemporal cortex, inferior parietal cortex and middle temporal areas. Comparing conditions, we revealed right lateralized parietal clusters, associated with novelty tuning, and left lateralized occipitotemporal clusters exhibiting higher activity for letters among digits discrimination, supporting the role of this area in letter processing. No distinct spatial patterns specific to orientation tuning were observed in comparison to novelty and category tuning. We proposed that expertise-dependent orientation-specific tuning mechanisms may operate within an embedded, spatially overlapping with coarse tuning neural framework, characterized by special spatiotemporal patterns.

neuroscience↗

bioRxiv2023

The Dietary Supplement Taurine Suppresses Ovarian Cancer Growth

Taurine, a non-proteogenic amino acid, and commonly used nutritional supplement can protect various tissues from degeneration associated with the action of the DNA-damaging chemotherapeutic agent cisplatin. Whether and how taurine protects human ovarian cancer (OC) cells from DNA damage caused by cisplatin is not well understood. We have found that OC ascites-derived cells contained significantly more intracellular taurine than cell cultures modeling OC. In culture, elevation of intracellular taurine concentration to OC ascites-cells-associated levels suppressed proliferation of various OC cell lines and patient-derived organoids, reduced glycolysis, and induced cell protection from cisplatin. Taurine cell protection was associated with decreased DNA damage in response to cisplatin. A combination of RNA sequencing, reverse phase protein arrays, live-cell microscopy, flow cytometry, and biochemical validation experiments provided evidence for taurine-mediated induction of mutant- or wild-type p53 binding to DNA, and activation of p53 effectors involved in negative regulation of the cell cycle (p21), and glycolysis (TIGAR). Paradoxically, taurines suppression of cell proliferation was associated with activation of pro-mitogenic signal transduction including ERK, mTOR, and increased mRNA expression of major DNA damage sensing molecules such as DNAPK, ATM and ATR. While inhibition of ERK or p53 did not interfere with taurines ability to protect cells from cisplatin, suppression of mTOR with Torin2, a clinically relevant inhibitor that also targets DNAPK and ATM/ATR, broke taurines cell protection. Our studies implicate that elevation of intracellular taurine could suppress cell growth, metabolism, and activate cell protective mechanisms involving mTOR and DNA damage sensing signal transduction.

cancer biology↗

bioRxiv2022

Chaperone-mediated Autophagy Deficiency Reprograms Cancer Metabolism Via TGFβ Signaling to drive Mesenchymal Tumor Growth

The role of chaperone-mediated autophagy (CMA) in cancer initiation and progression is not well understood due to the lack of a loss-of-function cancer models of LAMP2A, the key regulator of this process. Here, by generating an isoform-specific knockout of LAMP2A, we show that CMA deficiency promotes proliferation and tumor growth in human cancers of mesenchymal origin. Accordingly, we observed that LAMP2A diminishes in metastatic lesions compared to matched primary human tumors from the same patients. Loss of CMA enhanced TGF{beta} signaling in tumors, rewired the tumor metabolome to promote anabolic pathways and mitochondrial metabolism, meeting the metabolic requirements of rapid growth. Mechanistically, we show that TGF{beta}R2 enhances the enzymatic activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), to promote the generation of nucleotides. Consequently, pharmacological inhibition of TGF{beta}-signaling in LAMP2A-KO cells suppresses G6PD activity, mitochondrial metabolism, and proliferation to WT levels. Conversely, pharmacological inhibition of mitochondrial metabolism suppressed LAMP2A-KO driven proliferation. Overall, our study provides a molecular mechanism on the CMAs tumor-suppressive function by connecting two important oncogenic pathways, the TGF{beta} signaling and PPP metabolism, to the loss-of-function LAMP2A in mesenchymal cancer types.

cancer biology↗