Cell Survival Advantage in Cadmium Induced Carcinogenesis

镉诱发癌变中的细胞存活优势

• 批准号: 10403011
• 负责人: Chendil Damodaran
• 金额: $ 44.1万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403011
• 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/antagonist; 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.

项目摘要 暴露于镉（CD）与包括前列腺癌在内的一系列人类发病机理有关 （帽）。 CD暴露与异常前列腺血清抗原（PSA）之间的明显剂量反应关系，A 据报道，暴露于CD的男性中已有报道的CAP标记。但是，分子机制 CD暴露后的恶性细胞转化尚未确定，而CD之间的关联 在临床前和临床模型中，CAP均已确定。该应用的目的是 研究CD如何引起恶性细胞转化的潜在机制（从正常到 转化的细胞）和CD转化的细胞的肿瘤发生发展（转化为 细胞进行肿瘤发生）。我们的初步结果表明，在细胞转换期间，CD暴露 诱导的内质网（ER）压力，它触发了应力传感器的磷酸化 PERK和EIF2-α导致ATF4的激活，并启动自噬的诱导，以保护CD- 受损的细胞。虽然，可以看到自噬标记的诱导（ATG -12和ATG -16L，LC3B和LAMP1） 在CD处理的细胞中，由于失败自噬体和自溶性，自噬过程不完整 融合，这使受损的细胞扩散以进行转化。 p62在Cd-中的大量积累 处理过的细胞，也证实了自噬有缺陷的细胞。 siRNA或 药理抑制剂显着抑制转化细胞的生长，但在CD处理的正常 细胞或CD转化细胞表明EGFR激活起着关键作用，仅在细胞之后 转型。 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与体外发现相关。此外，蛋白质表达增加（atf- 与良性相比 前列腺增生和“正常”相邻组织。根据结果​​，我们假设慢性暴露 前列腺上皮细胞的CD会导致ER压力并随后自噬，导致增加 导致恶性细胞转化和转化的细胞EGFR激活的受损细胞的存活 在肿瘤发生中起重要作用。提出了三个具体目标：AIM-1：证明CD原因 ER应激又在前列腺上皮细胞转化过程中诱导自噬缺陷。 AIM 2：研究有缺陷自噬的受保护作用，这增加了CD受损细胞的存活率 在前列腺上皮细胞的转化过程中。 AIM-3：研究CD诱导的小鼠模型中的肿瘤发生 并验证人前列腺标本中的分子标记。