Cell Survival Advantage in Cadmium Induced Carcinogenesis

镉诱发癌变中的细胞存活优势

• 批准号: 10450743
• 负责人: Chendil Damodaran
• 金额: $ 44.14万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450743
• 关键词: Agreement; Antigens; Antioxidants; Autophagocytosis; Autophagosome; Benign Prostatic Hypertrophy; Biochemical; Blood; Cadmium; Cell Survival; Cells; Chronic; Clinical; Complex; Development; Dose; Elements; Endoplasmic Reticulum; Epidermal Growth Factor Receptor; Epithelial Cells; Eukaryotic Initiation Factors; Exposure to; Failure; Gleason Grade for Prostate Cancer; Goals; Growth; Human; Human Papillomavirus; Human Pathology; In Vitro; Inductively Coupled Plasma Mass Spectrometry; Knockout Mice; Laboratories; Malignant - descriptor; Malignant neoplasm of prostate; Measures; Modeling; Molecular; Molecular Analysis; Normal Cell; Pathogenesis; Pathologic; Patients; Pharmacology; Phenotype; Phosphorylation; Phosphotransferases; Play; Process; Production; Proliferating; Prostate; Prostatic Neoplasms; Protein Family; Proteins; Reactive Oxygen Species; Reporting; Role; SNAP receptor; Serum; Signal Transduction; Small Interfering RNA; Soil; Specimen; Stress; Tissues; Transducers; Tumor Tissue; United States; Urine; Xenograft Model; activating transcription factor 4; base; cancer cell; carcinogenesis; cell injury; cell transformation; endoplasmic reticulum stress; inhibitor; malignant phenotype; men; metallicity; metaplastic cell transformation; molecular marker; mouse model; overexpression; pre-clinical; protein expression; protein kinase R; response; sensor; superoxide dismutase 1; tumor growth; tumor xenograft; tumorigenesis; wasting

Project Summary Exposure to cadmium (Cd) is associated with a spectrum of human pathogenesis including the prostate cancer (CaP). A clear dose-response relation between Cd-exposure and abnormal prostate serum antigen (PSA), a marker for CaP have been reported in men exposed to Cd. However, the molecular mechanism underlying the malignant cell transformation following Cd exposure is yet to be determined, while the association between Cd and CaP in both pre-clinical and clinical models are well established. The goal of this application is to investigate the underlying mechanism of how Cd causes malignant cell transformation (from normal to transformed cells) and on the development of tumorigenesis by the Cd-transformed cells (transformed cells to tumorigenesis). Our preliminary results suggest that during cellular transformation, Cd exposure induced endoplasmic reticulum (ER)-stress, which triggered the phosphorylation of stress transducers including PERK and eIF2-α resulted in the activation of ATF4 and initiate the induction of autophagy that protects Cd- damaged cells. Although, induction of autophagy markers (Atg -12 and Atg-16L, LC3B and Lamp1) were seen in Cd-treated cells, the autophagy process is incomplete, due to failure autophagosome and autolysosome fusion, which allowed the damaged cell to proliferate for transformation. A massive accumulation of p62 in Cd- treated cells, which also confirmed the defective autophagy. Silencing EGFR activation by siRNA or pharmacological inhibitors significantly inhibited the growth in transformed cells, but not in Cd-treated normal cells or Cd- transforming cells suggesting that EGFR activation plays a critical role, only after cellular transformation. Xenograft tumor tissues generated by Cd-transformed cells expressed high levels of ATF-4, EGFR, p62 and LC3B in correlation with in vitro findings. Moreover, increased expression of the proteins (ATF- 4, EGFR, p62, and LC3B) in human CaP specimen’s agreement with Gleason sum in comparison with benign prostatic hyperplasia and “normal” adjacent tissues. Based on the results we hypothesize that Chronic exposure of prostate epithelial cells to Cd causes ER-stress and subsequently defective autophagy, leading to increased survival of damaged cells that result in malignant cell transformation and in transformed cell EGFR activation play a significant role in tumorigenesis. Three specific aims are proposed: Aim-1: To demonstrate that Cd causes ER-stress which in turn induced defective autophagy during the transformation of prostate epithelial cells. Aim 2: Investigate the protective role of defective autophagy, which increases the survival of Cd-damaged cells during the transformation of prostate epithelial cells. Aim-3: study Cd-induced tumorigenesis in mouse models and validate the molecular markers in human prostate specimens.

项目概要 接触镉 (Cd) 与一系列人类发病机制有关，包括前列腺癌 （帽）。镉暴露与异常前列腺血清抗原 (PSA) 之间存在明确的剂量反应关系， 据报道，暴露于镉的男性中存在 CaP 标记物。然而，其背后的分子机制 镉暴露后的恶性细胞转化尚未确定，而镉与镉之间的关联 和 CaP 在临床前和临床模型中均已成熟。该应用程序的目标是 研究镉如何引起恶性细胞转化（从正常细胞到 转化细胞）和镉转化细胞（转化细胞）肿瘤发生的发展 细胞肿瘤发生）。我们的初步结果表明，在细胞转化过程中，镉暴露 诱导内质网（ER）应激，触发应激传感器的磷酸化，包括 PERK 和 eIF2-α 导致 ATF4 激活并启动自噬的诱导，从而保护 Cd- 受损的细胞。尽管观察到自噬标记物（Atg -12 和 Atg-16L、LC3B 和 Lamp1）的诱导 在经镉处理的细胞中，由于自噬体和自溶酶体失效，自噬过程不完整 融合，使受损细胞能够增殖进行转化。 p62 在 Cd- 中大量积累 处理的细胞，这也证实了自噬缺陷。通过 siRNA 沉默 EGFR 激活或 药物抑制剂显着抑制转化细胞的生长，但不抑制镉处理的正常细胞的生长 细胞或 Cd 转化细胞表明 EGFR 激活发挥着关键作用，只有在细胞 转变。 Cd转化细胞产生的异种移植肿瘤组织表达高水平的ATF-4， EGFR、p62 和 LC3B 与体外研究结果相关。此外，蛋白质（ATF- 4、EGFR、p62 和 LC3B）在人 CaP 标本中与良性相比与格里森总和的一致性 前列腺增生和“正常”邻近组织。根据结果​​，我们假设慢性暴露 前列腺上皮细胞对 Cd 的吸收会导致 ER 应激，并随后导致自噬缺陷，导致 受损细胞的存活导致恶性细胞转化和转化细胞 EGFR 激活 在肿瘤发生中发挥重要作用。提出了三个具体目标： 目标 1：证明 Cd 会导致 内质网应激反过来在前列腺上皮细胞转化过程中诱导有缺陷的自噬。 目标 2：研究有缺陷的自噬的保护作用，它可以提高镉损伤细胞的存活率 在前列腺上皮细胞的转化过程中。 Aim-3：在小鼠模型中研究镉诱导的肿瘤发生 并验证人类前列腺样本中的分子标记。