Ceramide synthase as a therapy target in prostate cancer

神经酰胺合酶作为前列腺癌的治疗靶点

• 批准号: 7535569
• 负责人: ADRIANA HAIMOVITZ-FRIEDMAN
• 金额: $ 31.94万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-09 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7535569
• 关键词: ATM gene; ATM wt Allele; Acetates; Address; Animal Model; Animals; Antisense Oligonucleotides; Apoptosis; Apoptotic; Cell Death; Cell Line; Cells; Ceramides; Data; Development; Dose; Enzymes; Generations; Goals; Human; Induction of Apoptosis; Isoenzymes; LNCaP; Lactones; Lead; Malignant neoplasm of prostate; Mediating; Methods; Mitochondria; Molecular Target; Nude Mice; Oligonucleotides; PC3 cell line; Pathway interactions; Patients; Phorbol; Phorbol Esters; Phorbols; Phosphotransferases; Prostate; Prostatic Neoplasms; Protein Isoforms; Protein Kinase C; Radiation; Radiation therapy; Radiosensitization; Reagent; Relapse; Reporting; Research; Residual state; Resistance; Role; Signal Transduction; Site; Sphingolipids; Structure of base of prostate; Testing; Tissues; Treatment Protocols; Work; Xenograft Model; ataxia telangiectasia mutated protein; base; cancer cell; citrate carrier; clinical application; dihydroceramide desaturase; in vivo; irradiation; neoplastic cell; radiation resistance; research study; resistance mechanism; response; small molecule; tumor; tumor growth

DESCRIPTION (provided by applicant): The goal of this project is to develop modulators of radiation response able to overcome radiation resistance in human prostate tumor cells. Although radiation is able of permanently eradicate localized human prostate tumors, nearly 30% of patients treated with potentially curative radiotherapy relapse at the sites of the irradiated tumor due to residual radiation-resistant clonogens. In this application we propose to explore the mechanisms of resistance to radiation-induced apoptosis for the highly resistant, well-characterized human prostate cancer cell lines-LNCaP and CRW22Rv 1, Our preliminary data Show that activation of protein kinase C (PKC) isoforms by the phorbol ester 12,O-tetradecanoyl phorbol-13-acetate, (TPA), induces a moderate apoptotic response in these tumor cells, and sensitizes them towards radiation, induced apoptosis. We also showed that this apoptotic response is mediated by the enzyme ceramide synthase (CS) and de novo synthesis of ceramide. CS activity was previously reported by us to be negatively regulated by the Ataxia Telangiectasia-Mutated (ATM) gene. Our preliminary studies related to this application showed that in LNCaP and CRW22Rvl cells, TPA reduces ATM levels. We observed a similar reduction in ATM protein levels and radiosensitization using a diacylgycerol (DAG)-lactone, HK654, or antisense oligonucleotides to ATM (AS-ATM-ODNs). In this project, we propose to define the involvement of PKCa and PKC5 in TPAinduced apoptosis via activation of the ATM-CS pathway. We will also study the mechanisms of CS involvement in mitochondrial apoptosis, ceramide generation within the mitochondria, and the interaction between ceramide, PKC6 and/or Bax. Finally, we propose to study the role of the ATM-CS pathway in vivo in LNCaP and CWR22Rvl tumors growing orthotopically in nude mice. We will study the response to TPA ( radiation in response to both single-dose radiation as well as to fractionated radiation and will correlate tumor growth in these animals with tissue readouts. The proposed Specific Aims are interactive and address new and heretofore unknown mechanisms of TPA(radiation-induced cell death in prostate cancer cells and prostate animal models. Our research plan presents a signaling-based approach, to investigate new I hypotheses, about mechanisms of radiation resistance, which could provide a basis for modulation of the l radiation response in resistant human prostate tumor clones, with potential for clinical applications in the radiation management of human prostate cancer.

描述(申请人提供)：该项目的目标是开发辐射反应调节器，能够克服人类前列腺肿瘤细胞的辐射抗性。虽然放射治疗能够根治局限性的前列腺肿瘤，但近30%的接受潜在治疗的患者由于残留的耐辐射克隆细胞而在受照射的肿瘤部位复发。在这一应用中，我们建议探索高耐药的、具有良好特性的人前列腺癌LNCaP和CRW22Rv 1细胞株抵抗辐射诱导凋亡的机制。我们的初步数据表明，佛波酯12，O-十四酰佛波醇-13-乙酸酯(TPA)激活蛋白激酶C(PKC)亚型，在这些肿瘤细胞中诱导中等程度的凋亡反应，并使它们对辐射敏感，诱导凋亡。我们还表明，这种凋亡反应是由神经酰胺合成酶(CS)和神经酰胺从头合成介导的。我们以前报道过CS活性受共济失调毛细血管扩张突变(ATM)基因的负调控。我们与这一应用相关的初步研究表明，在LNCaP和CRW22Rv1细胞中，TPA降低ATM水平。我们观察到使用二酰基三甘油(DAG)-内酯HK654或ATM的反义寡核苷酸(AS-ATM-ODN)可以类似地降低ATM蛋白水平和放射增敏作用。在这个项目中，我们建议确定PKCA和PKC5在TPA通过激活ATM-CS通路而诱导的细胞凋亡中的作用。我们还将研究CS参与线粒体凋亡的机制，线粒体内神经酰胺的产生，以及神经酰胺、PKC6和/或Bax之间的相互作用。最后，我们建议研究ATM-CS途径在LNCaP和CWR22Rvl裸鼠原位生长肿瘤中的作用。我们将研究TPA(辐射)对单剂量辐射和分次辐射的反应，并将这些动物的肿瘤生长与组织读数相关联。提出的具体目标是互动的，并解决新的和迄今未知的TPA(辐射诱导前列腺癌细胞和前列腺动物模型中的细胞死亡)机制。我们的研究计划提出了一种基于信号转导的方法来研究有关辐射抵抗机制的新的I假说，这可能为调控L对前列腺癌耐药克隆的辐射反应提供基础，并有可能在临床上应用于前列腺癌的放射治疗。

项目成果

Chemotherapy-induced acute vascular injury involves intracellular generation of ROS via activation of the acid sphingomyelinase pathway.

• DOI: 10.1016/j.cellsig.2021.109969
• 发表时间: 2021-06
• 期刊: CELLULAR SIGNALLING
• 影响因子: 4.8
• 作者: Mizrachi, Aviram;Ben-Aharon, Irit;Li, Hongyan;Bar-Joseph, Hadas;Bodden, Chloe;Hikri, Elad;Popovtzer, Aron;Shalgi, Ruth;Haimovitz-Friedman, Adriana
• 通讯作者: Haimovitz-Friedman, Adriana

An Antitumor Immune Response Is Evoked by Partial-Volume Single-Dose Radiation in 2 Murine Models.

• DOI: 10.1016/j.ijrobp.2018.10.009
• 发表时间: 2019-03-01
• 期刊: International journal of radiation oncology, biology, physics
• 作者: Markovsky E;Budhu S;Samstein RM;Li H;Russell J;Zhang Z;Drill E;Bodden C;Chen Q;Powell SN;Merghoub T;Wolchok JD;Humm J;Deasy JO;Haimovitz-Friedman A
• 通讯作者: Haimovitz-Friedman A

Targeting acid sphingomyelinase with anti-angiogenic chemotherapy.

• DOI: 10.1016/j.cellsig.2016.09.010
• 发表时间: 2017-01
• 期刊: Cellular signalling
• 影响因子: 4.8
• 作者: Jacobi J;García-Barros M;Rao S;Rotolo JA;Thompson C;Mizrachi A;Feldman R;Manova K;Bielawska A;Bielawska J;Fuks Z;Kolesnick R;Haimovitz-Friedman A
• 通讯作者: Haimovitz-Friedman A