Plk1 in Chemo-resistance of Cancer

Plk1 在癌症化疗耐药中的作用

• 批准号: 8326573
• 负责人: XIAOQI LIU
• 金额: $ 25.09万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8326573
• 关键词: Affect; Apoptosis; Apoptotic; CDKN1A gene; Cell Cycle; Cell Cycle Arrest; Cell Cycle Progression; Cell Death; Cell Proliferation; Cells; Complex; Cultured Cells; Development; Doxorubicin; Drug resistance; Drug usage; Event; Exposure to; Failure; G1 Phase; G2 Phase; Goals; Knowledge; Lead; Life; Malignant Neoplasms; Mediating; Mitosis; Modeling; Molecular Chaperones; Normal Cell; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Play; Proteins; RNA Interference; Recovery; Regulation; Resistance; Resistance development; Role; S Phase; Survival Rate; Techniques; Testing; Tumor Suppression; Work; Xenograft Model; abstracting; cancer cell; cancer type; cell transformation; chemotherapeutic agent; chemotherapy; gain of function; human PLK1 protein; inhibitor/antagonist; knock-down; loss of function; multicatalytic endopeptidase complex; neoplastic cell; novel; oncoprotein p21; overexpression; prevent; response; tumor; tumor growth; tumor xenograft

DESCRIPTION (provided by applicant): Plk1 in chemoresistance of cancer Abstract: Paclitaxel and doxorubicin have been widely used to treat various cancers. However, one major problem for the failure of the chemotherapy is gradual development of resistance to drug-mediated cell death after prolonged exposure. Initially identified as a factor that leads to cell cycle arrest, p21CIP1/WAF1 can be induced by both p53-dependent and -independent mechanisms. As an inhibitor of cell proliferation, p21 plays an important role in drug-induced tumor suppression. However, it is now accepted that p21 can assume both pro- and anti- apoptotic functions after drug treatment depending on cellular context. For tumors with wild type p53, doxorubicin treatment causes activation of the p53/p21 pathway, resulting in cell cycle arrest and apoptosis. Inactivation of the p53/p21 pathway is required for subsequent recovery from doxorubicin-induced cell cycle arrest. In contrast, resistance to paclitaxel-mediated cell death has been correlated to elevated levels of p21 and knock-down of p21 restores paclitaxel sensitivity. Therefore, controlling p21 levels in tumor cells is critical for the efficacy of paclitaxel and doxorubicin, and possibly, other drugs. Because p21 is a short-lived and highly unstructured protein, modulation of its degradation rate significantly contributes to the regulation of its intracellular level. Association of p21 with the GTSE1/Hsp90/WISp39 complex in G2 phase and the Sgt1/Hsp90 complex in G1 phase protects it from degradation by the proteasome. In normal cells, p21 is degraded via the APCCdc20-dependent pathway in mitosis and the SCFSkp2-mediated pathway in S phase. However, p21 is stabilized in cancer cells throughout the cell cycle. Polo-like kinase 1 (Plk1), a critical regulator of many cell cycle-related events, is overexpressed in several types of cancers. Because we have identified GTSE1 and Sgt1 as two Plk1 substrates, we hypothesize that elevated levels of Plk1 in cancers promote p21 stability, thus contributing to chemoresistance. Our working model is as follows: Plk1 phosphorylation of GTSE1 prevents APCCdc20-mediated degradation of p21 in mitosis, and Plk1 phosphorylation of Sgt1 inhibits SCFSkp2-associated degradation of p21 in S phase. Both phosphorylation events lead to p21 stabilization, resulting in resistance of cancer cells to paclitaxel-mediated cell death. For cancer cells harboring WT p53, doxorubicin treatment results in cell cycle arrest. During the subsequent recovery, Plk1 phosphorylation of both Sgt1 and GTSE1 leads to inactivation of the p53 pathway to allow cell cycle re-entry, thus contributing to resistance of cancer cells to doxorubicin-mediated apoptosis. To test our hypothesis, we will first validate that Plk1 plays a critical role in resistance of cancer cells to paclitaxel/doxorubicin-mediated apoptosis. Mechanistically, we will determine how Plk1 phosphorylation of GTSE1 and Sgt1 regulates chemotherapy in both cultured cells and xenograft tumors. If successful, the predicted results will identify Plk1 as a novel target, inhibition of which will prevent chemoresistance, thus increasing the efficacy of chemotherapy.

描述（申请人提供）：Plk1在癌症化疗耐药中的作用 摘要：紫杉醇和阿霉素已广泛用于治疗多种癌症。然而，化疗失败的一个主要问题是长期接触药物介导的细胞死亡后逐渐产生耐药性。 p21CIP1/WAF1 最初被确定为导致细胞周期停滞的因子，可通过 p53 依赖性和非依赖性机制诱导。作为细胞增殖的抑制剂，p21 在药物诱导的肿瘤抑制中发挥着重要作用。然而，现在人们普遍认为，根据细胞环境，p21 在药物治疗后可以发挥促凋亡和抗凋亡功能。对于野生型 p53 肿瘤，阿霉素治疗会激活 p53/p21 通路，导致细胞周期停滞和细胞凋亡。 p53/p21 通路失活是随后从阿霉素诱导的细胞周期停滞中恢复所必需的。相反，对紫杉醇介导的细胞死亡的抵抗与 p21 水平升高相关，p21 的敲除可恢复紫杉醇敏感性。因此，控制肿瘤细胞中的 p21 水平对于紫杉醇和阿霉素以及其他药物的疗效至关重要。由于 p21 是一种寿命较短且高度非结构化的蛋白质，因此调节其降解速率可显着促进其细胞内水平的调节。 p21 与 G2 期 GTSE1/Hsp90/WISp39 复合物以及 G1 期 Sgt1/Hsp90 复合物的结合可保护其免受蛋白酶体降解。在正常细胞中，p21 在有丝分裂中通过 APCCdc20 依赖性途径和 S 期 SCFSkp2 介导的途径降解。然而，p21 在癌细胞的整个细胞周期中保持稳定。 Polo 样激酶 1 (Plk1) 是许多细胞周期相关事件的关键调节因子，在多种类型的癌症中过度表达。因为我们已经确定 GTSE1 和 Sgt1 是两种 Plk1 底物，所以我们假设癌症中 Plk1 水平升高会促进 p21 稳定性，从而导致化疗耐药。我们的工作模型如下：GTSE1 的 Plk1 磷酸化可防止有丝分裂中 APCCdc20 介导的 p21 降解，Sgt1 的 Plk1 磷酸化可抑制 S 期中 SCFSkp2 相关的 p21 降解。这两种磷酸化事件都会导致 p21 稳定，从而导致癌细胞对紫杉醇介导的细胞死亡产生抵抗力。对于携带 WT p53 的癌细胞，阿霉素治疗会导致细胞周期停滞。在随后的恢复过程中，Sgt1 和 GTSE1 的 Plk1 磷酸化导致 p53 通路失活，从而允许细胞周期重新进入，从而有助于癌细胞对阿霉素介导的细胞凋亡的抵抗。为了检验我们的假设，我们将首先验证 Plk1 在癌细胞抵抗紫杉醇/阿霉素介导的细胞凋亡中发挥关键作用。从机制上讲，我们将确定 GTSE1 和 Sgt1 的 Plk1 磷酸化如何调节培养细胞和异种移植肿瘤中的化疗。如果成功，预测结果将确定 Plk1 为新靶点，抑制 Plk1 将防止化疗耐药，从而提高化疗疗效。