Heat shock proteins in signaling and cancer

信号传导和癌症中的热休克蛋白

• 批准号: 7791657
• 负责人: Michael Y Sherman
• 金额: $ 35.56万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7791657
• 关键词: Affect; Animal Experiments; Animal Model; Animals; Breast; Bypass; Cancer cell line; Cancerous; Cell Aging; Cell Culture Techniques; Cell Proliferation; Cells; Dependence; Development; Epithelial; Epithelial Cells; Goals; Growth; Heat shock proteins; Heat-Shock Response; Human; Investigation; Knock-out; Knowledge; Lead; MCF10A cells; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mutation; Neoplastic Cell Transformation; Oncogenes; Oncogenic; PIK3CA gene; Pathway interactions; Process; Proliferating; Research; Resistance; Roche brand of trastuzumab; Role; Signal Pathway; Signal Transduction; TP53 gene; Testing; Work; Xenograft Model; Xenograft procedure; cancer cell; cancer type; cell transformation; in vivo; inhibitor/antagonist; knockout gene; malignant breast neoplasm; mouse model; novel; novel strategies; outcome forecast; prevent; programs; public health relevance; selective expression; senescence; small molecule; survivin; tumor

DESCRIPTION (provided by applicant): Expression of the major heat shock protein Hsp72 correlates with poor prognosis in many types of cancer, suggesting that Hsp72 can provide a selective advantage to cancer cells. However, our understanding of the distinct function of Hsp72 in cancer is very limited. The objective of this research program is to fill this gap of knowledge. Recently we established that Hsp72 in fact is essential for cancer cells, since depletion of Hsp72 prevented tumor formation in xenografts and precipitated growth inhibition and senescence in many cancer cell lines, but not in untransformed epithelial cells. Furthermore, we demonstrated that Hsp72 became essential for growth because of the permanent activation of PI3K or Ras oncogenic pathways in transformed cells. We hypothesize that elevated levels of Hsp72 seen in a variety of epithelial tumors function in preventing the endogenous oncogene-induced senescence program, thus allowing cancer cells to proliferate. Therefore, many tumors become "addicted" to high levels of Hsp72. The proposed project will elucidate mechanisms of the Hsp72- mediated control of the oncogene-induced senescence in cancer, using both cell culture, and animal models. A critical aspect of this work will be investigation the effects of NZ28, a novel inhibitor of the heat shock response developed by us, on tumors in animals. In Aim 1, we will establish the role of Hsp72 in the PI3K oncogenic pathway. We will test whether endogenous mPIK3CA oncogene determines dependence on Hsp72 of cancer lines established from human tumors. Further, we will elucidate signaling pathways controlled by Hsp72 that lead to the mPIK3CA-induced senescence. In Aim 2, we will establish the role of Hsp72 in neoplastic transformation by Her2 oncogene. Expression of Her2 oncogene in cells depleted of Hsp72 led to a paradoxical effect. Instead of transformation, these cells underwent growth arrest and senescence. Similar effect of Her2 was seen upon incubation of cells with an inhibitor of the heat shock response NZ28. Here, in both cell culture and animal experiments we will clarify how Hsp72 regulates Her2 signaling in tumors. We will investigate how Hsp72 knockout affects development of Her2-induced tumors in vivo. We will also establish whether the heat shock inhibitor NZ28 can cause tumor regression in a mouse model of Her2-positive breast tumor. Overall this program will clarify how Hsp72 controls tumor development. PUBLIC HEALTH RELEVANCE: A special mechanism called cell senescence has evolved that prevents proliferation of cells upon cancer development. Therefore, cells that undergo cancer transformation must acquire mutations that allow bypassing the senescence block. Here we will investigate mechanisms of bypassing cell senescence and develop small molecules that restore the block and prevent cancer.

描述（由申请人提供）：主要热休克蛋白HSP72的表达与许多类型的癌症的预后不良相关，这表明HSP72可以为癌细胞提供选择性的优势。但是，我们对HSP72在癌症中的独特功能的理解非常有限。该研究计划的目的是填补这一知识空白。最近，我们确定HSP72实际上对于癌细胞至关重要，因为HSP72的耗竭阻止了异种移植物中的肿瘤形成，并且在许多癌细胞系中降低了生长抑制和衰老，但在未转换的上皮细胞中却不是。此外，我们证明了HSP72对于转化细胞中PI3K或RAS致癌途径的永久激活而成为生长至关重要。我们假设在各种上皮肿瘤中看到的HSP72水平升高在防止内源性癌基因诱发的衰老程序中起作用，从而使癌细胞得以增殖。因此，许多肿瘤变成了高水平的HSP72。拟议的项目将使用细胞培养和动物模型来阐明HSP72介导的癌症诱导的癌症衰老的机制。这项工作的一个关键方面将是研究NZ28的影响，NZ28是一种新型的热休克反应抑制剂对动物肿瘤的影响。在AIM 1中，我们将确定HSP72在PI3K致癌途径中的作用。我们将测试内源性MPIK3CA致癌基因是否决定了对人类肿瘤建立的癌症HSP72的依赖性。此外，我们将阐明由HSP72控制的信号通路，从而导致MPIK3CA诱导的衰老。在AIM 2中，我们将确定HSP72在HER2癌基因肿瘤转化中的作用。 HSP72耗尽的细胞中HER2癌基因的表达导致了矛盾的作用。这些细胞没有转化，而是经历了生长停滞和衰老。 HER2在与热休克反应NZ28的抑制剂中孵育时也观察到了类似的作用。在这里，在细胞培养和动物实验中，我们将阐明HSP72如何调节肿瘤中的HER2信号传导。我们将研究HSP72敲除如何影响HER2诱导的体内肿瘤的发育。我们还将确定热休克抑制剂NZ28是否会在HER2阳性乳腺肿瘤的小鼠模型中引起肿瘤消退。总体而言，该计划将阐明HSP72如何控制肿瘤的发展。 公共卫生相关性： 一种称为细胞衰老的特殊机制已经进化出来，可防止癌症发育时细胞的增殖。因此，经历癌症转化的细胞必须获得允许绕过衰老阻滞的突变。在这里，我们将研究绕过细胞衰老的机制，并发展出恢复障碍并预防癌症的小分子。