المؤلفون: Upasana Ray, Debarshi Roy, Ling Jin, Prabhu Thirusangu, Julie Staub, Yinan Xiao, Eleftheria Kalogera, Andrea E. Wahner Hendrickson, Grace D. Cullen, Krista Goergen, Ann L. Oberg, Viji Shridhar

المصدر: Journal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-16 (2021)

مصطلحات موضوعية: Ovarian cancer, metastasis, Group III phospholipase A2, chemosensitivity, autophagy, primary cilia, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Aberrant lipogenicity and deregulated autophagy are common in most advanced human cancer and therapeutic strategies to exploit these pathways are currently under consideration. Group III Phospholipase A2 (sPLA2-III/PLA2G3), an atypical secretory PLA2, is recognized as a regulator of lipid metabolism associated with oncogenesis. Though recent studies reveal that high PLA2G3 expression significantly correlates with poor prognosis in several cancers, however, role of PLA2G3 in ovarian cancer (OC) pathogenesis is still undetermined. Methods CRISPR-Cas9 and shRNA mediated knockout and knockdown of PLA2G3 in OC cells were used to evaluate lipid droplet (LD) biogenesis by confocal and Transmission electron microscopy analysis, and the cell viability and sensitization of the cells to platinum-mediated cytotoxicity by MTT assay. Regulation of primary ciliation by PLA2G3 downregulation both genetically and by metabolic inhibitor PFK-158 induced autophagy was assessed by immunofluorescence-based confocal analysis and immunoblot. Transient transfection with GFP-RFP-LC3B and confocal analysis was used to assess the autophagic flux in OC cells. PLA2G3 knockout OVCAR5 xenograft in combination with carboplatin on tumor growth and metastasis was assessed in vivo. Efficacy of PFK158 alone and with platinum drugs was determined in patient-derived primary ascites cultures expressing PLA2G3 by MTT assay and immunoblot analysis. Results Downregulation of PLA2G3 in OVCAR8 and 5 cells inhibited LD biogenesis, decreased growth and sensitized cells to platinum drug mediated cytotoxicity in vitro and in in vivo OVCAR5 xenograft. PLA2G3 knockdown in HeyA8MDR-resistant cells showed sensitivity to carboplatin treatment. We found that both PFK158 inhibitor-mediated and genetic downregulation of PLA2G3 resulted in increased number of percent ciliated cells and inhibited cancer progression. Mechanistically, we found that PFK158-induced autophagy targeted PLA2G3 to restore primary cilia in OC cells. Of clinical relevance, PFK158 also induces percent ciliated cells in human-derived primary ascites cells and reduces cell viability with sensitization to chemotherapy. Conclusions Taken together, our study for the first time emphasizes the role of PLA2G3 in regulating the OC metastasis. This study further suggests the therapeutic potential of targeting phospholipases and/or restoration of PC for future OC treatment and the critical role of PLA2G3 in regulating ciliary function by coordinating interface between lipogenesis and metastasis.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1756-9966Test

الوصول الحر: https://doaj.org/article/c51f205913f048ecae91afeecbaec90fTest

المؤلفون: Sarit Pal, Anatoliy Gashev, Debarshi Roy

المصدر: Biology Open, Vol 11, Iss 7 (2022)

مصطلحات موضوعية: gpcr, histamine receptor 2, nuclear localization, Science, Biology (General), QH301-705.5

الوصف: Histamine exerts its physiological functions through its four receptor subtypes. In this work, we report the subcellular localization of histamine receptor 2 (H2R), a G protein-coupled receptor (GPCR), which is expressed in a wide variety of cell and tissue types. A growing number of GPCRs have been shown to be localized in the nucleus and contribute toward transcriptional regulation. In this study, for the first time, we demonstrate the nuclear localization of H2R in lymphatic endothelial cells. In the presence of its ligand, we show significant upregulation of H2R nuclear translocation kinetics. Using fluorescently tagged histamine, we explored H2R-histamine binding interaction, which exhibits a critical role in this translocation event. Altogether, our results highlight the previously unrecognized nuclear localization pattern of H2R. At the same time, H2R as a GPCR imparts many unresolved questions, such as the functional relevance of this localization, and whether H2R can contribute directly to transcriptional regulation and can affect lymphatic specific gene expression. H2R blockers are commonly used medications that recently have shown significant side effects. Therefore, it is imperative to understand the precise molecular mechanism of H2R biology. In this aspect, our present data shed new light on the unexplored H2R signaling mechanisms. This article has an associated First Person interview with the first author of the paper.

وصف الملف: electronic resource

العلاقة: http://bio.biologists.org/content/11/7/bio059191Test; https://doaj.org/toc/2046-6390Test

الوصول الحر: https://doaj.org/article/d283a500b73b4da5b799430956c6f8dcTest

المؤلفون: Sanjay Sarkar, Archie Taylor, Pratik Dutta, Meghna Bajaj, Justin Nash, Martha Ravola, Sofia Ievleva, Cardarius Llyod, Praise Ola, Brenita Jenkins, Bidisha Sengupta, Debarshi Roy

المصدر: Health Science Reports, Vol 4, Iss 3, Pp n/a-n/a (2021)

مصطلحات موضوعية: COVID‐19, disparity, Mississippi, obesity, SARS‐CoV2, Medicine

الوصف: Abstract Background and Aims According to the World Health Organization (WHO), more than 75.7 million confirmed cases of coronavirus disease 2019 (COVID‐19), a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), have been reported so far. Researchers are working relentlessly to find effective solutions to this catastrophe, using genomic sequence‐based investigation, immunological analysis, and more. The role of health disparity has also emerged as an intriguing factor that made a huge impact on the lives of people. Methods We analyzed various factors that triggered the health disparity in the United States of America along with the rate of COVID‐19 morbidity and mortality. Furthermore, we have also focused on the State of Mississippi, which is suffering from an extreme health disparity. Data have been obtained from publicly available data sources including, Center for Disease Control and Prevention and Mississippi State Department of Health. Correlation analysis of the dataset has been performed using R software. Results Our analysis suggested that the COVID‐19 infection rate per 100 000 people is directly correlated with the increasing number of the African American population in the United States. We have found a strong correlation between the obesity and the COVID‐19 cases as well. All the counties in Mississippi demonstrate a strong correlation between a higher number of African American population to COVID‐19 cases and obesity. Our data also indicate that a higher number of African American populations are facing socioeconomic disadvantages, which enhance their chances of becoming vulnerable to pre‐existing ailments such as obesity, type‐2 diabetes, and cardiovascular diseases. Conclusion We proposed a possible explanation of increased COVID‐19 infectivity in the African American population in the United States. This work has highlighted the intriguing factors that increased the health disparity at the time of the COVID‐19 pandemic.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2398-8835Test

الوصول الحر: https://doaj.org/article/58dadd8f76024a9b887052c5a5b6d9ceTest

المؤلفون: John E. Piletz, Yuhan Mao, Debarshi Roy, Bilal Qizilbash, Eurielle Nkamssi, Enleyona Weir, Jessica Graham, Mary Emmanuel, Suwaira Iqbal, Kellie Brue, Bidisha Sengupta

المصدر: Nutrients, Vol 13, Iss 2, p 488 (2021)

مصطلحات موضوعية: Brassica oleracea, cruciferous, Taraxacum officinale, Spinacia oleracea, Lactuca sativa, vegetable juice, Nutrition. Foods and food supply, TX341-641

الوصف: Juicing vegetables is thought to be an anticancer treatment. Support exists for a rank order of anticancer greens (kale > dandelion > lettuce > spinach) based on degrees of bioavailability of different phytochemicals, also offset by some noxious molecules (i.e., calcium-oxalate). We developed a new in vitro transepithelial anti-neuroblastoma model system. The juices were diluted as predicted once in the small intestine. They were applied to apical Caco-2Bbe1 cells atop dividing SH-SY5Y neuroblastoma cells, and changes in transepithelial electrical resistance (TEER) and cell growth were considered with juice spectroscopies. Studied first in monoculture, kale and dandelion were the most cytostatic juices on SH-SY5Ys, lettuce showed no effect, and high (4.2%) spinach was cytotoxic. In co-culture, high (4.2%) kale was quickest (three days) to inhibit neuroblastoma growth. By five days, dandelion and kale were equally robust. Lettuce showed small anti-proliferative effects at five days and spinach remained cytotoxic. Spinach’s cytotoxicity corresponded with major infrared bands indicative of oxalate. Kale juice uniquely induced reactive oxygen species and S-phase cell cycle arrest in SH-SY5Y. The superiority of kale and dandelion was also apparent on the epithelium, because raising TEER levels is considered healthy. Kale’s unique features corresponded with a major fluorescent peak that co-eluted with kaempferol during high performance liquid chromatography. Because the anticancer rank order was upheld, the model appears validated for screening anticancer juices.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2072-6643/13/2/488Test; https://doaj.org/toc/2072-6643Test

الوصول الحر: https://doaj.org/article/a0846fa573b4465589843927fb609e02Test

المؤلفون: Upasana Ray (3763864), Debarshi Roy (10920043), Ling Jin (133762), Prabhu Thirusangu (10920046), Julie Staub (10920049), Yinan Xiao (7336949), Eleftheria Kalogera (10920052), Andrea E. Wahner Hendrickson (10920055), Grace D. Cullen (10920058), Krista Goergen (277812), Ann L. Oberg (217897), Viji Shridhar (278465)

مصطلحات موضوعية: Biophysics, Biochemistry, Microbiology, Cell Biology, Genetics, Molecular Biology, Physiology, Pharmacology, Biotechnology, Cancer, Hematology, Virology, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, Ovarian cancer, metastasis, Group III phospholipase A2, chemosensitivity, autophagy, primary cilia

الوصف: Additional file 1.

العلاقة: https://figshare.com/articles/journal_contribution/Additional_file_1_of_Group_III_phospholipase_A2_downregulation_attenuated_survival_and_metastasis_in_ovarian_cancer_and_promotes_chemo-sensitization/14728585Test

الإتاحة: https://doi.org/10.6084/m9.figshare.14728585.v1Test

المؤلفون: Priyadarshini Dasgupta, Lisa Kuhn, Ephraim Massawe, Mason Williams, Julian Perrone, Pratik Dutta, Debarshi Roy

المصدر: Environmental Quality Management. 32:161-171

مصطلحات موضوعية: Public Health, Environmental and Occupational Health, Management, Monitoring, Policy and Law, Pollution, Waste Management and Disposal

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::26c4972c88559924f1bbb1e4a06cc5abTest
https://doi.org/10.1002/tqem.21884Test

المؤلفون: Viji Shridhar, Anirban K. Mitra, Nagarajan Kannan, Scott H. Kaufmann, Jamie N. Bakkum-Gamez, James W. Purcell, Xiaonan Hou, S. John Weroha, Bhaskar Roy, Debarshi Roy, Julie K. Staub, Prabhu Thirusangu, Sayantani Sarkar Bhattacharya, Subramanyam Dasari, Yinan Xiao, Ling Jin, Deok-Beom Jung, Upasana Ray

الوصف: Dissemination of ovarian cancer cells can lead to inoperable metastatic lesions in the bowel and omentum that cause patient death. Here we show that LRRC15, a type-I 15-leucine–rich repeat-containing membrane protein, highly overexpressed in ovarian cancer bowel metastases compared with matched primary tumors and acts as a potent promoter of omental metastasis. Complementary models of ovarian cancer demonstrated that LRRC15 expression leads to inhibition of anoikis-induced cell death and promotes adhesion and invasion through matrices that mimic omentum. Mechanistically, LRRC15 interacted with β1-integrin to stimulate activation of focal adhesion kinase (FAK) signaling. As a therapeutic proof of concept, targeting LRRC15 with the specific antibody–drug conjugate ABBV-085 in both early and late metastatic ovarian cancer cell line xenograft models prevented metastatic dissemination, and these results were corroborated in metastatic patient-derived ovarian cancer xenograft models. Furthermore, treatment of 3D-spheroid cultures of LRRC15-positive patient-derived ascites with ABBV-085 reduced cell viability. Overall, these data uncover a role for LRRC15 in promoting ovarian cancer metastasis and suggest a novel and promising therapy to target ovarian cancer metastases.Significance: This study identifies that LRRC15 activates β1-integrin/FAK signaling to promote ovarian cancer metastasis and shows that the LRRC15-targeted antibody–drug conjugate ABBV-085 suppresses ovarian cancer metastasis in preclinical models.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::2762054a1279e40777a463a4112c3b6bTest
https://doi.org/10.1158/0008-5472.c.6513550.v1Test

المؤلفون: Viji Shridhar, Anirban K. Mitra, Nagarajan Kannan, Scott H. Kaufmann, Jamie N. Bakkum-Gamez, James W. Purcell, Xiaonan Hou, S. John Weroha, Bhaskar Roy, Debarshi Roy, Julie K. Staub, Prabhu Thirusangu, Sayantani Sarkar Bhattacharya, Subramanyam Dasari, Yinan Xiao, Ling Jin, Deok-Beom Jung, Upasana Ray

الوصف: Supplementary Data from Targeting LRRC15 Inhibits Metastatic Dissemination of Ovarian Cancer

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::68910d3e0504c6863b8cac86e24ae5cdTest
https://doi.org/10.1158/0008-5472.22430101.v1Test

المؤلفون: Debarshi Roy, Prabhu Thirusangu, Ann L. Oberg, Krista M. Goergen, Viji Shridhar, Andrea E. Wahner Hendrickson, Grace D. Cullen, Upasana Ray, Yinan Xiao, Ling Jin, Julie Staub, Eleftheria Kalogera

المصدر: Journal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-16 (2021)
Journal of Experimental & Clinical Cancer Research : CR

مصطلحات موضوعية: Cancer Research, autophagy, Cell Survival, Pyridines, medicine.disease_cause, Metastasis, Mice, primary cilia, Downregulation and upregulation, Microscopy, Electron, Transmission, Ovarian cancer, medicine, Animals, Humans, metastasis, MTT assay, Viability assay, Neoplasm Metastasis, Cytotoxicity, RC254-282, Cell Proliferation, Platinum, Ovarian Neoplasms, Chemistry, Research, Group III Phospholipases A2, Lipogenesis, Cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Lipid Droplets, medicine.disease, Gene Expression Regulation, Neoplastic, chemosensitivity, Group III phospholipase A2, Oncology, Cancer research, Quinolines, Heterografts, Female, CRISPR-Cas Systems, Carcinogenesis

الوصف: Background Aberrant lipogenicity and deregulated autophagy are common in most advanced human cancer and therapeutic strategies to exploit these pathways are currently under consideration. Group III Phospholipase A2 (sPLA2-III/PLA2G3), an atypical secretory PLA2, is recognized as a regulator of lipid metabolism associated with oncogenesis. Though recent studies reveal that high PLA2G3 expression significantly correlates with poor prognosis in several cancers, however, role of PLA2G3 in ovarian cancer (OC) pathogenesis is still undetermined. Methods CRISPR-Cas9 and shRNA mediated knockout and knockdown of PLA2G3 in OC cells were used to evaluate lipid droplet (LD) biogenesis by confocal and Transmission electron microscopy analysis, and the cell viability and sensitization of the cells to platinum-mediated cytotoxicity by MTT assay. Regulation of primary ciliation by PLA2G3 downregulation both genetically and by metabolic inhibitor PFK-158 induced autophagy was assessed by immunofluorescence-based confocal analysis and immunoblot. Transient transfection with GFP-RFP-LC3B and confocal analysis was used to assess the autophagic flux in OC cells. PLA2G3 knockout OVCAR5 xenograft in combination with carboplatin on tumor growth and metastasis was assessed in vivo. Efficacy of PFK158 alone and with platinum drugs was determined in patient-derived primary ascites cultures expressing PLA2G3 by MTT assay and immunoblot analysis. Results Downregulation of PLA2G3 in OVCAR8 and 5 cells inhibited LD biogenesis, decreased growth and sensitized cells to platinum drug mediated cytotoxicity in vitro and in in vivo OVCAR5 xenograft. PLA2G3 knockdown in HeyA8MDR-resistant cells showed sensitivity to carboplatin treatment. We found that both PFK158 inhibitor-mediated and genetic downregulation of PLA2G3 resulted in increased number of percent ciliated cells and inhibited cancer progression. Mechanistically, we found that PFK158-induced autophagy targeted PLA2G3 to restore primary cilia in OC cells. Of clinical relevance, PFK158 also induces percent ciliated cells in human-derived primary ascites cells and reduces cell viability with sensitization to chemotherapy. Conclusions Taken together, our study for the first time emphasizes the role of PLA2G3 in regulating the OC metastasis. This study further suggests the therapeutic potential of targeting phospholipases and/or restoration of PC for future OC treatment and the critical role of PLA2G3 in regulating ciliary function by coordinating interface between lipogenesis and metastasis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d2312f39716829d872e4f2d1f69a840aTest
https://doaj.org/article/c51f205913f048ecae91afeecbaec90fTest

المؤلفون: Debarshi Roy, Bidisha Sengupta, Pragnya Biswas, Justin Lovett, Laken Simington, Darrell R. Fry, Kaelin Travis

المصدر: Current topics in medicinal chemistry.

مصطلحات موضوعية: Drug Discovery, General Medicine

الوصف: Abstract: Polyhydroxy compounds are secondary metabolites that are ubiquitous in plants of high-er genera. They possess therapeutic properties against a wide spectrum of diseases, including can-cers, neurodegenerative disorders, atherosclerosis, as well as cardiovascular disease. The phyto-chemical flavonol (a type of flavonoid) kaempferol (KMP) (3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4Hchromen-4-one) is abundant in cruciferous vegetables, including broccoli, kale, spinach, and wa-tercress, as well as in herbs like dill, chives, and tarragon. KMP is predominantly hydrophobic in nature due to its diphenylpropane structure (a characteristic feature of flavonoids). Recent findings have indicated the promise of applying KMP in disease prevention due to its potential antioxidant, antimutagenic, antifungal, and antiviral activities. In the literature, there is evidence that KMP ex-erts its anticancer effects by modulating critical elements in cellular signal transduction pathways linked to apoptosis, inflammation, angiogenesis, and metastasis in cancer cells without affecting the viability of normal cells. It has been shown that KMP triggers cancer cell death by several mecha-nisms, including cell cycle arrest, caspase activation, metabolic alteration, and impacting human te-lomerase reverse-transcriptase gene expression. This review is aimed at providing critical insights into the influence of KMP on the intracellular cascades that regulate metabolism and signaling in breast, ovarian, and cervical cancer cells.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aff58745e6c6a3809d5cc1a7b49a9ca3Test
https://pubmed.ncbi.nlm.nih.gov/36082856Test