Tumor Necrosis Factor-alpha Signaling in Breast Cancer

乳腺癌中的肿瘤坏死因子-α 信号转导

• 批准号: 7020701
• 负责人: Alakananda Basu
• 金额: $ 23.05万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-04 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7020701
• 关键词: apoptosis; biological signal transduction; breast neoplasms; carcinogenesis; cell line; clinical research; cysteine endopeptidases; cytokine receptors; neoplastic growth; phosphatidylinositol 3 kinase; protein kinase C; protein protein interaction; serine threonine protein kinase; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Apoptosis is a highly orchestrated cell suicidal program required to maintain a balance between cell proliferation and cell death. Tumor necrosis factor-a (TNF), a pleotropic cytokine, plays an important role in immunesurveillance. The interaction of TNF with its receptors triggers activation of a family of cysteine proteases or caspases that are essential for the execution of cell death by apoptosis. The ability to evade cell death pathway is a critical event in cancer progression. Various pro- and antiapoptotic signal transduction pathways regulate activation of caspases by TNF. Protein kinase C (PKC), a family of serine/threonine kinases, plays a critical role in growth factor signal transduction pathway. During our previous funding period, we have shown that novel PKC isozymes act as anti-apoptotic proteins to inhibit cell death by TNF. The abundance of novel PKCs, however, was not sufficient to explain cellular sensitivity/resistance to TNF. A deregulation in Akt/protein kinase B (PKB) signal transduction pathway has been associated with the genesis of several cancers, including breast cancer although the molecular mechanism(s) by which this signaling pathway contributes to breast cancer pathogenesis is incompletely understood. We hypothesize that the PKC signal transduction pathway cooperates with components of the phosphatidylinositol 3-kinase (PI3K) pathway, such as PKB to regulate cell survival and cell death. The overall objective of this grant proposal is to delineate how a deregulation in PI3K/PKB signaling pathway that exists in breast cancer cells influences anti-apoptotic signaling by PKC. The long-term objective is to develop strategies to intervene with these pathways to inhibit progression of breast cancer.

描述（由申请人提供）：细胞凋亡是一种高度精心策划的细胞自杀程序，需要维持细胞增殖和细胞死亡之间的平衡。肿瘤坏死因子-a (TNF) 是一种多效性细胞因子，在免疫监视中发挥着重要作用。 TNF 与其受体的相互作用触发半胱氨酸蛋白酶或半胱天冬酶家族的激活，这对于通过细胞凋亡执行细胞死亡至关重要。逃避细胞死亡途径的能力是癌症进展中的关键事件。各种促凋亡和抗凋亡信号转导途径通过 TNF 调节半胱天冬酶的激活。蛋白激酶 C (PKC) 是丝氨酸/苏氨酸激酶家族，在生长因子信号转导途径中发挥着关键作用。在我们之前的资助期间，我们已经证明新型 PKC 同工酶可以作为抗凋亡蛋白来抑制 TNF 引起的细胞死亡。然而，大量的新型 PKC 不足以解释细胞对 TNF 的敏感性/耐药性。 Akt/蛋白激酶 B (PKB) 信号转导途径的失调与包括乳腺癌在内的多种癌症的发生有关，尽管该信号转导途径导致乳腺癌发病机制的分子机制尚不完全清楚。我们假设 PKC 信号转导途径与磷脂酰肌醇 3-激酶 (PI3K) 途径的成分（例如 PKB）协同调节细胞存活和细胞死亡。该拨款提案的总体目标是阐明乳腺癌细胞中存在的 PI3K/PKB 信号通路的失调如何影响 PKC 的抗凋亡信号传导。 长期目标是制定干预这些途径的策略，以抑制乳腺癌的进展。