Kailash Chandra Mangalhara

Bio: Kailash Chandra Mangalhara is an academic researcher from Jawaharlal Nehru University. The author has contributed to research in topics: Mitochondrial DNA & Cancer cell. The author has an hindex of 8, co-authored 11 publications receiving 296 citations. Previous affiliations of Kailash Chandra Mangalhara include Salk Institute for Biological Studies.

Curcumin decreases Warburg effect in cancer cells by down-regulating pyruvate kinase M2 via mTOR-HIF1α inhibition.

Abstract: Warburg effect is an emerging hallmark of cancer cells with pyruvate kinase M2 (PKM2) as its key regulator. Curcumin is an extensively-studied anti-cancer compound, however, its role in affecting cancer metabolism remains poorly understood. Herein, we show that curcumin inhibits glucose uptake and lactate production (Warburg effect) in a variety of cancer cell lines by down-regulating PKM2 expression, via inhibition of mTOR-HIF1α axis. Stable PKM2 silencing revealed that PKM2 is required for Warburg effect and proliferation of cancer cells. PKM2 over-expression abrogated the effects of curcumin, demonstrating that inhibition of Warburg effect by curcumin is PKM2-mediated. High PKM2 expression correlated strongly with poor overall survival in cancer, suggesting the requirement of PKM2 in cancer progression. The study unravels novel PKM2-mediated inhibitory effect of curcumin on metabolic capacities of cancer cells. To the best of our knowledge, this is the first study linking curcumin with PKM2-driven cancer glycolysis, thus, providing new perspectives into the mechanism of its anticancer activity.

Mitochondrial DNA Stress Signalling Protects the Nuclear Genome.

Abstract: The mammalian genome comprises nuclear DNA (nDNA) derived from both parents and mitochondrial DNA (mtDNA) that is maternally inherited and encodes essential proteins required for oxidative phosphorylation. Thousands of copies of the circular mtDNA are present in most cell types that are packaged by TFAM into higher-order structures called nucleoids1. Mitochondria are also platforms for antiviral signalling2 and, due to their bacterial origin, mtDNA and other mitochondrial components trigger innate immune responses and inflammatory pathology2,3. We showed previously that cytoplasmic release of mtDNA activates the cGAS–STING–TBK1 pathway resulting in interferon-stimulated gene (ISG) expression that promotes antiviral immunity4. Here, we find that persistent mtDNA stress is not associated with basally activated NF-κB signalling or interferon gene expression typical of an acute antiviral response. Instead, a specific subset of ISGs that includes Parp9 remains activated by the unphosphorylated form of ISGF3 that enhances nDNA damage and repair responses. In cultured primary fibroblasts and cancer cells, the chemotherapeutic drug doxorubicin causes mtDNA damage and release, which leads to cGAS–STING–dependent ISG activation. In addition, mtDNA stress in TFAM-deficient mouse melanoma cells produces tumours that are more resistant to doxorubicin in vivo. Finally, Tfam+/− mice exposed to ionizing radiation exhibit enhanced nDNA repair responses in spleen. Therefore, we propose that damage to and subsequent release of mtDNA elicits a protective signalling response that enhances nDNA repair in cells and tissues, suggesting that mtDNA is a genotoxic stress sentinel. Persistent mitochondrial DNA stress is shown to upregulate nuclear DNA damage and repair responses via activation of the cGAS–STING pathway and a subset of interferon-stimulated genes.

DNA Methyltransferase1 (DNMT1) Isoform3 methylates mitochondrial genome and modulates its biology.

Abstract: Here we demonstrate localization of the isoform3 of DNA Methyltransferase1 (DNMT1) enzyme to mitochondria, instead of isoform1 as reported earlier. The fused DNMT1-isoform1, reported earlier to localize in mitochondria, surprisingly showed its exclusive presence inside the nucleus after its ectopic expression; and failed to localize in mitochondria. On the other hand, ectopically expressed DNMT1-isoform3 targeted itself to mitochondria and subsequently methylated CpG regions in the mitochondrial genome. In addition, overexpression of DNMT1-isoform3 affected mitochondrial biology and regulated its function. Under different conditions of oxidative and nutritional stress, this isoform was down-regulated, resulting in hypomethylation of mitochondrial genome. Our study reveals how DNMT1-isoform3, instead of isoform1, is responsible for mtDNA methylation, influencing its biology.

Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq

Abstract: Single-cell expression profiles of melanoma Tumors harbor multiple cell types that are thought to play a role in the development of resistance to drug treatments. Tirosh et al. used single-cell sequencing to investigate the distribution of these differing genetic profiles within melanomas. Many cells harbored heterogeneous genetic programs that reflected two different states of genetic expression, one of which was linked to resistance development. Following drug treatment, the resistance-linked expression state was found at a much higher level. Furthermore, the environment of the melanoma cells affected their gene expression programs. Science, this issue p. 189 Melanoma cells show transcriptional heterogeneity. To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells. Malignant cells within the same tumor displayed transcriptional heterogeneity associated with the cell cycle, spatial context, and a drug-resistance program. In particular, all tumors harbored malignant cells from two distinct transcriptional cell states, such that tumors characterized by high levels of the MITF transcription factor also contained cells with low MITF and elevated levels of the AXL kinase. Single-cell analyses suggested distinct tumor microenvironmental patterns, including cell-to-cell interactions. Analysis of tumor-infiltrating T cells revealed exhaustion programs, their connection to T cell activation and clonal expansion, and their variability across patients. Overall, we begin to unravel the cellular ecosystem of tumors and how single-cell genomics offers insights with implications for both targeted and immune therapies.

A Review of Curcumin and Its Derivatives as Anticancer Agents.

Abstract: Cancer is the second leading cause of death in the world and one of the major public health problems. Despite the great advances in cancer therapy, the incidence and mortality rates of cancer remain high. Therefore, the quest for more efficient and less toxic cancer treatment strategies is still at the forefront of current research. Curcumin, the active ingredient of the Curcuma longa plant, has received great attention over the past two decades as an antioxidant, anti-inflammatory, and anticancer agent. In this review, a summary of the medicinal chemistry and pharmacology of curcumin and its derivatives in regard to anticancer activity, their main mechanisms of action, and cellular targets has been provided based on the literature data from the experimental and clinical evaluation of curcumin in cancer cell lines, animal models, and human subjects. In addition, the recent advances in the drug delivery systems for curcumin delivery to cancer cells have been highlighted.

The cGAS-STING pathway as a therapeutic target in inflammatory diseases.

Abstract: The cGAS-STING signalling pathway has emerged as a key mediator of inflammation in the settings of infection, cellular stress and tissue damage Underlying this broad involvement of the cGAS-STING pathway is its capacity to sense and regulate the cellular response towards microbial and host-derived DNAs, which serve as ubiquitous danger-associated molecules Insights into the structural and molecular biology of the cGAS-STING pathway have enabled the development of selective small-molecule inhibitors with the potential to target the cGAS-STING axis in a number of inflammatory diseases in humans Here, we outline the principal elements of the cGAS-STING signalling cascade and discuss the general mechanisms underlying the association of cGAS-STING activity with various autoinflammatory, autoimmune and degenerative diseases Finally, we outline the chemical nature of recently developed cGAS and STING antagonists and summarize their potential clinical applications

Intratumoral heterogeneity in cancer progression and response to immunotherapy.

Abstract: Most (if not all) tumors emerge and progress under a strong evolutionary pressure imposed by trophic, metabolic, immunological, and therapeutic factors The relative impact of these factors on tumor evolution changes over space and time, ultimately favoring the establishment of a neoplastic microenvironment that exhibits considerable genetic, phenotypic, and behavioral heterogeneity in all its components Here, we discuss the main sources of intratumoral heterogeneity and its impact on the natural history of the disease, including sensitivity to treatment, as we delineate potential strategies to target such a detrimental feature of aggressive malignancies The many levels of heterogeneity within tumors dictate their response to therapy and should be considered in future therapeutic regimes

A Diverse Array of Cancer-Associated MTOR Mutations Are Hyperactivating and Can Predict Rapamycin Sensitivity

Abstract: Genes encoding components of the PI3K-AKT-mTOR signaling axis are frequently mutated in cancer, but few mutations have been characterized in MTOR, the gene encoding the mTOR kinase. Using publicly available tumor genome sequencing data, we generated a comprehensive catalog of mTOR pathway mutations in cancer, identifying 33 MTOR mutations that confer pathway hyperactivation. The mutations cluster in six distinct regions in the C-terminal half of mTOR and occur in multiple cancer types, with one cluster particularly prominent in kidney cancer. The activating mutations do not affect mTOR complex assembly, but a subset reduces binding to the mTOR inhibitor DEPTOR. mTOR complex 1 (mTORC1) signaling in cells expressing various activating mutations remains sensitive to pharmacologic mTOR inhibition, but is partially resistant to nutrient deprivation. Finally, cancer cell lines with hyperactivating MTOR mutations display heightened sensitivity to rapamycin both in culture and in vivo xenografts, suggesting that such mutations confer mTOR pathway dependency.