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  1. Article: Cell-Free RNA as a Novel Biomarker for Response to Therapy in Head & Neck Cancer.

    Tosevska, Anela / Morselli, Marco / Basak, Saroj K / Avila, Luis / Mehta, Parag / Wang, Marilene B / Srivatsan, Eri S / Pellegrini, Matteo

    Frontiers in oncology

    2022  Volume 12, Page(s) 869108

    Abstract: Liquid biopsies are gaining more traction as non-invasive tools for the diagnosis and monitoring of cancer. In a new paradigm of cancer treatment, a synergistic botanical drug combination (APG-157) consisting of multiple molecules, is emerging as a new ... ...

    Abstract Liquid biopsies are gaining more traction as non-invasive tools for the diagnosis and monitoring of cancer. In a new paradigm of cancer treatment, a synergistic botanical drug combination (APG-157) consisting of multiple molecules, is emerging as a new class of cancer therapeutics, targeting multiple pathways and providing a durable clinical response, wide therapeutic window and high level of safety. Monitoring the efficacy of such drugs involves assessing multiple molecules and cellular events simultaneously. We report, for the first time, a methodology that uses circulating plasma cell-free RNA (cfRNA) as a sensitive indicator of patient response upon drug treatment. Plasma was collected from six patients with head and neck cancer (HNC) and four healthy controls receiving three doses of 100 or 200 mg APG-157 or placebo through an oral mucosal route, before treatment and on multiple points post-dosing. Circulating cfRNA was extracted from plasma at 0-, 3- and 24-hours post-treatment, followed by RNA sequencing. We performed comparative analyses of the circulating transcriptome and were able to detect significant perturbation following APG-157 treatment. Transcripts associated with inflammatory response, leukocyte activation and cytokine were upregulated upon treatment with APG-157 in cancer patients, but not in healthy or placebo-treated patients. A platelet-related transcriptional signature could be detected in cancer patients but not in healthy individuals, indicating a platelet-centric pathway involved in the development of HNC. These results from a Phase 1 study are a proof of principle of the utility of cfRNAs as non-invasive circulating biomarkers for monitoring the efficacy of APG-157 in HNC.
    Language English
    Publishing date 2022-05-06
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2022.869108
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Gigaxonin Suppresses Epithelial-to-Mesenchymal Transition of Human Cancer Through Downregulation of Snail.

    Veena, Mysore S / Gahng, Jungmo J / Alani, Mustafa / Ko, Albert Y / Basak, Saroj K / Liu, Isabelle Y / Hwang, Kimberly J / Chatoff, Jenna R / Venkatesan, Natarajan / Morselli, Marco / Yan, Weihong / Ali, Ibraheem / Kaczor-Urbanowicz, Karolina Elżbieta / Gowda, Bhavani Shankara / Frost, Patrick / Pellegrini, Matteo / Moatamed, Neda A / Wilczynski, Sharon P / Bomont, Pascale /
    Wang, Marilene B / Shin, Daniel Sanghoon / Srivatsan, Eri S

    Cancer research communications

    2024  Volume 4, Issue 3, Page(s) 706–722

    Abstract: Gigaxonin is an E3 ubiquitin ligase that plays a role in cytoskeletal stability. Its role in cancer is not yet clearly understood. Our previous studies of head and neck cancer had identified gigaxonin interacting with p16 for NFκB ubiquitination. To ... ...

    Abstract Gigaxonin is an E3 ubiquitin ligase that plays a role in cytoskeletal stability. Its role in cancer is not yet clearly understood. Our previous studies of head and neck cancer had identified gigaxonin interacting with p16 for NFκB ubiquitination. To explore its role in cancer cell growth suppression, we analyzed normal and tumor DNA from cervical and head and neck cancers. There was a higher frequency of exon 8 SNP (c.1293 C>T, rs2608555) in the tumor (46% vs. 25% normal, P = 0.011) pointing to a relationship to cancer. Comparison of primary tumor with recurrence and metastasis did not reveal a statistical significance. Two cervical cancer cell lines, ME180 and HT3 harboring exon 8 SNP and showing T allele expression correlated with higher gigaxonin expression, reduced in vitro cell growth and enhanced cisplatin sensitivity in comparison with C allele expressing cancer cell lines. Loss of gigaxonin expression in ME180 cells through CRISPR-Cas9 or siRNA led to aggressive cancer cell growth including increased migration and Matrigel invasion. The in vitro cell growth phenotypes were reversed with re-expression of gigaxonin. Suppression of cell growth correlated with reduced Snail and increased e-cadherin expression. Mouse tail vein injection studies showed increased lung metastasis of cells with low gigaxonin expression and reduced metastasis with reexpression of gigaxonin. We have found an association between C allele expression and RNA instability and absence of multimeric protein formation. From our results, we conclude that gigaxonin expression is associated with suppression of epithelial-mesenchymal transition through inhibition of Snail.
    Significance: Our results suggest that GAN gene exon 8 SNP T allele expression correlates with higher gigaxonin expression and suppression of aggressive cancer cell growth. There is downregulation of Snail and upregulation of e-cadherin through NFκB ubiquitination. We hypothesize that exon 8 T allele and gigaxonin expression could serve as diagnostic markers of suppression of aggressive growth of head and neck cancer.
    MeSH term(s) Humans ; Animals ; Mice ; Down-Regulation/genetics ; Cell Line, Tumor ; Head and Neck Neoplasms/drug therapy ; Epithelial-Mesenchymal Transition/genetics ; Cadherins/genetics
    Chemical Substances Cadherins
    Language English
    Publishing date 2024-02-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2767-9764
    ISSN (online) 2767-9764
    DOI 10.1158/2767-9764.CRC-23-0331
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: The cell based therapy and the policy implications in India.

    Mukhopadhyay, Bratati / Basak, Saroj K / Ganguly, Nirmal K

    Journal of stem cells

    2011  Volume 6, Issue 3, Page(s) 155–179

    Abstract: The recent scientific development using stem or other differentiated cells has generated great hopes for treatment of various diseases. Major thrust has been given to formulate country specific laws and regulations considering international guidelines to ...

    Abstract The recent scientific development using stem or other differentiated cells has generated great hopes for treatment of various diseases. Major thrust has been given to formulate country specific laws and regulations considering international guidelines to conduct research and clinical applications of "Cell Based Therapy" (CBT) all over the world. Attempts have made in this review to discuss the current policies that are practiced by various countries in the areas related to CBT with special emphasis on CBT related research and development in India. The two major funding agencies of Government of India e.g. Department of Biotechnology (DBT) and Indian Council of Medical Research (ICMR), have jointly formulated the "Guidelines for Stem Cell Research and Therapy" in 2007 which requires update and revision. Based on the review of the current world scenario of CBT research and development, suggestions have been made for the development of a new CBT policy that will help in progress of research and patient treatment in India.
    MeSH term(s) Animals ; Biomedical Research/economics ; Biomedical Research/legislation & jurisprudence ; Cell Transplantation/adverse effects ; Cell Transplantation/economics ; Cell Transplantation/legislation & jurisprudence ; Dendritic Cells/transplantation ; Endothelial Cells/transplantation ; Genetic Therapy/legislation & jurisprudence ; Government Regulation ; Health Policy/economics ; Health Policy/legislation & jurisprudence ; Humans ; India ; Patient Safety/legislation & jurisprudence ; Practice Guidelines as Topic ; Research Support as Topic/legislation & jurisprudence ; Stem Cell Research/legislation & jurisprudence ; Stem Cell Transplantation/legislation & jurisprudence
    Language English
    Publishing date 2011
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ISSN 1556-8539
    ISSN 1556-8539
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: A sensitive LC-MS assay using derivatization with boron trifluoride to quantify curcuminoids in biological samples

    Yoon, Alexander J / Wu, Haiqiang / Pan, Roy D / Teter, Bruce / Cipolla, Jack / Chang, Edwin / Avila, Luis Z / Basak, Saroj K / Srivatsan, Eri S / Wang, Marilene B / Cole, Greg M / Frautschy, Sally A / Hampton, Phillip D / Faull, Kym F

    Analytical biochemistry. 2020 May 01, v. 596

    2020  

    Abstract: A procedure is described to measure curcumin (C), demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), tetrahydrocurcumim (TC) and their glucuronidated metabolites (CG, DMCG, and BDMCG) in plasma, brain, liver and tumor samples. The procedure involves ... ...

    Abstract A procedure is described to measure curcumin (C), demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), tetrahydrocurcumim (TC) and their glucuronidated metabolites (CG, DMCG, and BDMCG) in plasma, brain, liver and tumor samples. The procedure involves converting the analytes to their boron difluoride derivatives and analyzing them by combined liquid chromatography coupled to an ion trap mass spectrometer operating in the negative ion MSn scan mode. The method has superb limits of detection of 0.01 nM for all curcuminoids and 0.5 nM for TC and the glucuroniated metabolites, and several representative chromatograms of biological samples containing these analytes are provided. In addition, the pharmacokinetic profile of these compounds in one human who daily consumed an over-the-counter curcuminoid product shows the peak and changes in circulating concentrations achieved by this mode of administration.
    Keywords blood plasma ; boron ; brain ; chemical species ; curcumin ; derivatization ; detection limit ; humans ; liquid chromatography ; liver ; mass spectrometry ; metabolites ; neoplasms ; pharmacokinetics ; spectrometers
    Language English
    Dates of publication 2020-0501
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 1110-1
    ISSN 1096-0309 ; 0003-2697
    ISSN (online) 1096-0309
    ISSN 0003-2697
    DOI 10.1016/j.ab.2020.113636
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: A sensitive LC-MS assay using derivatization with boron trifluoride to quantify curcuminoids in biological samples.

    Yoon, Alexander J / Wu, Haiqiang / Pan, Roy D / Teter, Bruce / Cipolla, Jack / Chang, Edwin / Avila, Luis Z / Basak, Saroj K / Srivatsan, Eri S / Wang, Marilene B / Cole, Greg M / Frautschy, Sally A / Hampton, Phillip D / Faull, Kym F

    Analytical biochemistry

    2020  Volume 596, Page(s) 113636

    Abstract: A procedure is described to measure curcumin (C), demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), tetrahydrocurcumim (TC) and their glucuronidated metabolites (CG, DMCG, and BDMCG) in plasma, brain, liver and tumor samples. The procedure involves ... ...

    Abstract A procedure is described to measure curcumin (C), demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), tetrahydrocurcumim (TC) and their glucuronidated metabolites (CG, DMCG, and BDMCG) in plasma, brain, liver and tumor samples. The procedure involves converting the analytes to their boron difluoride derivatives and analyzing them by combined liquid chromatography coupled to an ion trap mass spectrometer operating in the negative ion MS
    MeSH term(s) Animals ; Boranes/chemistry ; Chromatography, Liquid ; Diarylheptanoids/blood ; Diarylheptanoids/chemistry ; Diarylheptanoids/isolation & purification ; Healthy Volunteers ; Humans ; Mass Spectrometry ; Mice ; Molecular Structure
    Chemical Substances Boranes ; Diarylheptanoids ; boron trifluoride (7JGD48PX8P)
    Language English
    Publishing date 2020-02-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1110-1
    ISSN 1096-0309 ; 0003-2697
    ISSN (online) 1096-0309
    ISSN 0003-2697
    DOI 10.1016/j.ab.2020.113636
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Dysregulation of hsa-miR-34a and hsa-miR-449a leads to overexpression of PACS-1 and loss of DNA damage response (DDR) in cervical cancer.

    Veena, Mysore S / Raychaudhuri, Santanu / Basak, Saroj K / Venkatesan, Natarajan / Kumar, Parameet / Biswas, Roopa / Chakrabarti, Rita / Lu, Jing / Su, Trent / Gallagher-Jones, Marcus / Morselli, Marco / Fu, Haiqing / Pellegrini, Matteo / Goldstein, Theodore / Aladjem, Mirit I / Rettig, Matthew B / Wilczynski, Sharon P / Shin, Daniel Sanghoon / Srivatsan, Eri S

    The Journal of biological chemistry

    2020  Volume 295, Issue 50, Page(s) 17169–17186

    Abstract: We have observed overexpression of PACS-1, a cytosolic sorting protein in primary cervical tumors. Absence of exonic mutations and overexpression at the RNA level suggested a transcriptional and/or posttranscriptional regulation. University of California ...

    Abstract We have observed overexpression of PACS-1, a cytosolic sorting protein in primary cervical tumors. Absence of exonic mutations and overexpression at the RNA level suggested a transcriptional and/or posttranscriptional regulation. University of California Santa Cruz genome browser analysis of PACS-1 micro RNAs (miR), revealed two 8-base target sequences at the 3' terminus for hsa-miR-34a and hsa-miR-449a. Quantitative RT-PCR and Northern blotting studies showed reduced or loss of expression of the two microRNAs in cervical cancer cell lines and primary tumors, indicating dysregulation of these two microRNAs in cervical cancer. Loss of PACS-1 with siRNA or exogenous expression of hsa-miR-34a or hsa-miR-449a in HeLa and SiHa cervical cancer cell lines resulted in DNA damage response, S-phase cell cycle arrest, and reduction in cell growth. Furthermore, the siRNA studies showed that loss of PACS-1 expression was accompanied by increased nuclear γH2AX expression, Lys
    MeSH term(s) DNA Damage ; Drug Resistance, Neoplasm ; Female ; G1 Phase ; HeLa Cells ; Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; RNA, Neoplasm/genetics ; RNA, Neoplasm/metabolism ; S Phase Cell Cycle Checkpoints ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Uterine Cervical Neoplasms/genetics ; Uterine Cervical Neoplasms/metabolism ; Uterine Cervical Neoplasms/pathology ; Vesicular Transport Proteins/genetics ; Vesicular Transport Proteins/metabolism
    Chemical Substances MIRN34 microRNA, human ; MIRN449 microRNA, human ; MicroRNAs ; PACS1 protein, human ; RNA, Neoplasm ; TP53 protein, human ; Tumor Suppressor Protein p53 ; Vesicular Transport Proteins
    Language English
    Publishing date 2020-10-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.RA120.014048
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: A randomized, phase 1, placebo-controlled trial of APG-157 in oral cancer demonstrates systemic absorption and an inhibitory effect on cytokines and tumor-associated microbes.

    Basak, Saroj K / Bera, Alakesh / Yoon, Alexander J / Morselli, Marco / Jeong, Chan / Tosevska, Anela / Dong, Tien S / Eklund, Michael / Russ, Eric / Nasser, Hassan / Lagishetty, Venu / Guo, Rong / Sajed, Dipti / Mudgal, Sharmila / Mehta, Parag / Avila, Luis / Srivastava, Meera / Faull, Kym / Jacobs, Jonathan /
    Pellegrini, Matteo / Shin, Daniel Sanghoon / Srivatsan, Eri S / Wang, Marilene B

    Cancer

    2020  Volume 126, Issue 8, Page(s) 1668–1682

    Abstract: Background: Although curcumin's effect on head and neck cancer has been studied in vitro and in vivo, to the authors' knowledge its efficacy is limited by poor systemic absorption from oral administration. APG-157 is a botanical drug containing multiple ...

    Abstract Background: Although curcumin's effect on head and neck cancer has been studied in vitro and in vivo, to the authors' knowledge its efficacy is limited by poor systemic absorption from oral administration. APG-157 is a botanical drug containing multiple polyphenols, including curcumin, developed under the US Food and Drug Administration's Botanical Drug Development, that delivers the active components to oromucosal tissues near the tumor target.
    Methods: A double-blind, randomized, placebo-controlled, phase 1 clinical trial was conducted with APG-157 in 13 normal subjects and 12 patients with oral cancer. Two doses, 100 mg or 200 mg, were delivered transorally every hour for 3 hours. Blood and saliva were collected before and 1 hour, 2 hours, 3 hours, and 24 hours after treatment. Electrocardiograms and blood tests did not demonstrate any toxicity.
    Results: Treatment with APG-157 resulted in circulating concentrations of curcumin and analogs peaking at 3 hours with reduced IL-1β, IL-6, and IL-8 concentrations in the salivary supernatant fluid of patients with cancer. Salivary microbial flora analysis showed a reduction in Bacteroidetes species in cancer subjects. RNA and immunofluorescence analyses of tumor tissues of a subject demonstrated increased expression of genes associated with differentiation and T-cell recruitment to the tumor microenvironment.
    Conclusions: The results of the current study suggested that APG-157 could serve as a therapeutic drug in combination with immunotherapy.
    Lay summary: Curcumin has been shown to suppress tumor cells because of its antioxidant and anti-inflammatory properties. However, its effectiveness has been limited by poor absorption when delivered orally. Subjects with oral cancer were given oral APG-157, a botanical drug containing multiple polyphenols, including curcumin. Curcumin was found in the blood and in tumor tissues. Inflammatory markers and Bacteroides species were found to be decreased in the saliva, and immune T cells were increased in the tumor tissue. APG-157 is absorbed well, reduces inflammation, and attracts T cells to the tumor, suggesting its potential use in combination with immunotherapy drugs.
    MeSH term(s) Absorption, Physiological/drug effects ; Adult ; Aged ; Antineoplastic Agents/therapeutic use ; Curcumin/therapeutic use ; Cytokines/antagonists & inhibitors ; Cytokines/metabolism ; Double-Blind Method ; Female ; Humans ; Inflammation/metabolism ; Male ; Microbiota/drug effects ; Middle Aged ; Mouth Neoplasms/drug therapy ; Mouth Neoplasms/metabolism ; Polyphenols/therapeutic use ; Saliva/microbiology ; Tumor Microenvironment/drug effects
    Chemical Substances Antineoplastic Agents ; Cytokines ; Polyphenols ; Curcumin (IT942ZTH98)
    Language English
    Publishing date 2020-02-05
    Publishing country United States
    Document type Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1429-1
    ISSN 1097-0142 ; 0008-543X ; 1934-662X
    ISSN (online) 1097-0142
    ISSN 0008-543X ; 1934-662X
    DOI 10.1002/cncr.32644
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Cystatin E/M Suppresses Tumor Cell Growth through Cytoplasmic Retention of NF-κB.

    Soh, Hendrick / Venkatesan, Natarajan / Veena, Mysore S / Ravichandran, Sandhiya / Zinabadi, Alborz / Basak, Saroj K / Parvatiyar, Kislay / Srivastava, Meera / Liang, Li-Jung / Gjertson, David W / Torres, Jorge Z / Moatamed, Neda A / Srivatsan, Eri S

    Molecular and cellular biology

    2016  Volume 36, Issue 12, Page(s) 1776–1792

    Abstract: We and others have shown that the cystatin E/M gene is inactivated in primary human tumors, pointing to its role as a tumor suppressor gene. However, the molecular mechanism of tumor suppression is not yet understood. Using plasmid-directed cystatin E/M ... ...

    Abstract We and others have shown that the cystatin E/M gene is inactivated in primary human tumors, pointing to its role as a tumor suppressor gene. However, the molecular mechanism of tumor suppression is not yet understood. Using plasmid-directed cystatin E/M gene overexpression, a lentivirus-mediated tetracycline-inducible vector system, and human papillomavirus 16 (HPV 16) E6 and E7 gene-immortalized normal human epidermal keratinocytes, we demonstrated intracellular and non-cell-autonomous apoptotic growth inhibition of tumor cell lines and that growth inhibition is associated with cytoplasmic retention of NF-κB. We further demonstrated decreased phosphorylation of IκB kinase (IKKβ) and IκBα in the presence of tumor necrosis factor alpha (TNF-α), confirming the role of cystatin E/M in the regulation of the NF-κB signaling pathway. Growth suppression of nude mouse xenograft tumors carrying a tetracycline-inducible vector system was observed with the addition of doxycycline in drinking water, confirming that the cystatin E/M gene is a tumor suppressor gene. Finally, immunohistochemical analyses of cervical carcinoma in situ and primary tumors have shown a statistically significant inverse relationship between the expression of cystatin E/M and cathepsin L and a direct relationship between the loss of cystatin E/M expression and nuclear expression of NF-κB. We therefore propose that the cystatin E/M suppressor gene plays an important role in the regulation of NF-κB.
    MeSH term(s) Animals ; Cathepsin L/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Cystatin M/genetics ; Cystatin M/metabolism ; Cytoplasm/metabolism ; Doxycycline/administration & dosage ; Female ; Gene Expression Regulation, Neoplastic ; Genetic Vectors/pharmacology ; HeLa Cells ; Humans ; I-kappa B Proteins/metabolism ; Lentivirus/genetics ; Mice ; Mice, Nude ; NF-kappa B/metabolism ; Neoplasm Transplantation ; Phosphorylation ; Signal Transduction ; Tumor Necrosis Factor-alpha/metabolism ; Uterine Cervical Neoplasms/genetics ; Uterine Cervical Neoplasms/metabolism ; Uterine Cervical Neoplasms/pathology
    Chemical Substances CST6 protein, human ; Cystatin M ; I-kappa B Proteins ; NF-kappa B ; TNF protein, human ; Tumor Necrosis Factor-alpha ; CTSL protein, human (EC 3.4.22.15) ; Cathepsin L (EC 3.4.22.15) ; Doxycycline (N12000U13O)
    Language English
    Publishing date 2016-05-31
    Publishing country United States
    Document type Journal Article
    ZDB-ID 779397-2
    ISSN 1098-5549 ; 0270-7306
    ISSN (online) 1098-5549
    ISSN 0270-7306
    DOI 10.1128/MCB.00878-15
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Cystatin E/M Suppresses Tumor Cell Growth through Cytoplasmic Retention of NF-κB

    Soh, Hendrick / Venkatesan, Natarajan / Veena, Mysore S. / Ravichandran, Sandhiya / Zinabadi, Alborz / Basak, Saroj K. / Parvatiyar, Kislay / Srivastava, Meera / Liang, Li-Jung / Gjertson, David W. / Torres, Jorge Z. / Moatamed, Neda A. / Srivatsan, Eri S.

    Molecular and Cellular Biology. 2016 June 1, v. 36, no. 12 p.1776-1792

    2016  

    Abstract: We and others have shown that the cystatin E/M gene is inactivated in primary human tumors, pointing to its role as a tumor suppressor gene. However, the molecular mechanism of tumor suppression is not yet understood. Using plasmid-directed cystatin E/M ... ...

    Abstract We and others have shown that the cystatin E/M gene is inactivated in primary human tumors, pointing to its role as a tumor suppressor gene. However, the molecular mechanism of tumor suppression is not yet understood. Using plasmid-directed cystatin E/M gene overexpression, a lentivirus-mediated tetracycline-inducible vector system, and human papillomavirus 16 (HPV 16) E6 and E7 gene-immortalized normal human epidermal keratinocytes, we demonstrated intracellular and non-cell-autonomous apoptotic growth inhibition of tumor cell lines and that growth inhibition is associated with cytoplasmic retention of NF-κB. We further demonstrated decreased phosphorylation of IκB kinase (IKKβ) and IκBα in the presence of tumor necrosis factor alpha (TNF-α), confirming the role of cystatin E/M in the regulation of the NF-κB signaling pathway. Growth suppression of nude mouse xenograft tumors carrying a tetracycline-inducible vector system was observed with the addition of doxycycline in drinking water, confirming that the cystatin E/M gene is a tumor suppressor gene. Finally, immunohistochemical analyses of cervical carcinoma in situ and primary tumors have shown a statistically significant inverse relationship between the expression of cystatin E/M and cathepsin L and a direct relationship between the loss of cystatin E/M expression and nuclear expression of NF-κB. We therefore propose that the cystatin E/M suppressor gene plays an important role in the regulation of NF-κB.
    Keywords Human papillomavirus type 16 ; apoptosis ; cathepsin L ; cell growth ; doxycycline ; gene overexpression ; growth retardation ; humans ; immunohistochemistry ; keratinocytes ; mice ; neoplasm cells ; phosphorylation ; suppressor genes ; tumor necrosis factor-alpha ; tumor suppressor genes ; uterine cervical neoplasms ; xenotransplantation
    Language English
    Dates of publication 2016-0601
    Size p. 1776-1792.
    Publishing place Taylor & Francis
    Document type Article ; Online
    ZDB-ID 779397-2
    ISSN 1098-5549 ; 0270-7306
    ISSN (online) 1098-5549
    ISSN 0270-7306
    DOI 10.1128/MCB.00878-15
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  10. Article ; Online: Cancer stem cells, microRNAs, and therapeutic strategies including natural products.

    Vira, Darshni / Basak, Saroj K / Veena, Mysore S / Wang, Marilene B / Batra, Raj K / Srivatsan, Eri S

    Cancer metastasis reviews

    2012  Volume 31, Issue 3-4, Page(s) 733–751

    Abstract: Embryonic stem cells divide continuously and differentiate into organs through the expression of specific transcription factors at specific time periods. Differentiated adult stem cells on the other hand remain in quiescent state and divide by receiving ... ...

    Abstract Embryonic stem cells divide continuously and differentiate into organs through the expression of specific transcription factors at specific time periods. Differentiated adult stem cells on the other hand remain in quiescent state and divide by receiving cues from the environment (extracellular matrix or niche), as in the case of wound healing from tissue injury or inflammation. Similarly, it is believed that cancer stem cells (CSCs), forming a smaller fraction of the tumor bulk, also remain in a quiescent state. These cells are capable of initiating and propagating neoplastic growth upon receiving environmental cues, such as overexpression of growth factors, cytokines, and chemokines. Candidate CSCs express distinct biomarkers that can be utilized for their identification and isolation. This review focuses on the known and candidate cancer stem cell markers identified in various solid tumors and the promising future of disease management and therapy targeted at these markers. The review also provides details on the differential expression of microRNAs (miRNAs), and the miRNA- and natural product-based therapies that could be applied for the treatment of cancer stem cells.
    MeSH term(s) AC133 Antigen ; Aldehyde Dehydrogenase 1 Family ; Animals ; Antigens, CD/analysis ; Basigin/analysis ; Biological Products/therapeutic use ; Carrier Proteins/analysis ; Glycoproteins/analysis ; Humans ; Hyaluronan Receptors/analysis ; Isoenzymes/analysis ; Membrane Proteins/analysis ; MicroRNAs/physiology ; Neoplastic Stem Cells/chemistry ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/physiology ; Peptides/analysis ; Polycomb Repressive Complex 1/physiology ; Proto-Oncogene Proteins/physiology ; Reactive Oxygen Species/metabolism ; Retinal Dehydrogenase/analysis ; Stem Cells/physiology ; Thyroid Hormones/analysis ; Thyroid Hormone-Binding Proteins
    Chemical Substances AC133 Antigen ; Antigens, CD ; Biological Products ; Bmi1 protein, mouse ; Carrier Proteins ; Glycoproteins ; Hyaluronan Receptors ; Isoenzymes ; Membrane Proteins ; MicroRNAs ; Peptides ; Proto-Oncogene Proteins ; Reactive Oxygen Species ; Thyroid Hormones ; Basigin (136894-56-9) ; Aldehyde Dehydrogenase 1 Family (EC 1.2.1) ; ALDH1A1 protein, human (EC 1.2.1.36) ; ALDH1A1 protein, mouse (EC 1.2.1.36) ; Retinal Dehydrogenase (EC 1.2.1.36) ; Polycomb Repressive Complex 1 (EC 2.3.2.27)
    Language English
    Publishing date 2012-07-03
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
    ZDB-ID 604857-2
    ISSN 1573-7233 ; 0167-7659
    ISSN (online) 1573-7233
    ISSN 0167-7659
    DOI 10.1007/s10555-012-9382-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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