Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India.
Centre for Advance Research, Faculty of Medicine, King George's Medical University, Lucknow-226003, India.
Chem Biol Interact. 2023 Mar 1;373:110373. doi: 10.1016/j.cbi.2023.110373. Epub 2023 Feb 1.
Lung cancer is an aggressive malignancy and the leading cause of cancer-related deaths. Benzo[a]pyrene (B[a]P), a polycyclic hydrocarbon, plays a pivotal role in lung carcinogenesis. Uncovering the molecular mechanism underlying the pathophysiology of B[a]P induced malignancy is crucial. Male Sprague Dawley rats were induced with B[a]P to generate a lung cancer model. The B[a]P administered rats show increased body and lung weight, loss of normal pulmonary architecture, and decreased survival. This study demonstrated that B[a]P upregulates activating transcription factor-6 (ATF6) and C/EBP Homologous Protein (CHOP) and induces endoplasmic reticulum (ER) stress. B[a]P also dysregulated mitochondrial homeostasis by upregulating, PTEN-induced putative kinase-1 (PINK1) and Parkin. B[a]P affected the levels of superoxide dismutase (SOD), reduced glutathione (GSH), malondialdehyde (MDA), and increased oxidative stress. B[a]P exposure downregulated Kelch-like ECH-associated protein 1 (Keap1) and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and Heme oxygenase-1(HO1). The metabolomic study identified that biosynthesis of nucleotide, amino acids, pentose phosphate pathway (PPP), tricarboxylic acid cycle (TCA), and glutathione metabolism were up-accumulated. On the other hand, lower accumulation of fatty acids e.g., palmitic acid, stearic acid, and oleic acid were reported in the B[a]P induced group. Overall, the results of this study indicate that B[a]P treatment affects several signaling and metabolic pathways, whose dysregulation might be involved in lung cancer induction.
肺癌是一种侵袭性恶性肿瘤，也是癌症相关死亡的主要原因。苯并[a]芘（B[a]P）是一种多环芳烃，在肺癌发生中起着关键作用。揭示 B[a]P 诱导恶性肿瘤的病理生理学的分子机制至关重要。雄性 Sprague Dawley 大鼠用 B[a]P 诱导产生肺癌模型。给予 B[a]P 的大鼠表现出体重和肺重增加、正常肺结构丧失和生存率降低。本研究表明，B[a]P 上调激活转录因子 6（ATF6）和 C/EBP 同源蛋白（CHOP），并诱导内质网（ER）应激。B[a]P 还通过上调 PTEN 诱导的假定激酶-1（PINK1）和 Parkin 来扰乱线粒体稳态。B[a]P 影响超氧化物歧化酶（SOD）、还原型谷胱甘肽（GSH）、丙二醛（MDA）的水平，并增加氧化应激。B[a]P 暴露下调 Kelch-like ECH-associated protein 1（Keap1），上调核因子红细胞 2 相关因子 2（Nrf2）和血红素加氧酶-1（HO1）。代谢组学研究表明，核苷酸、氨基酸、戊糖磷酸途径（PPP）、三羧酸循环（TCA）和谷胱甘肽代谢的生物合成被上调。另一方面，B[a]P 诱导组中报道了脂肪酸的积累减少，例如棕榈酸、硬脂酸和油酸。总的来说，这项研究的结果表明，B[a]P 处理会影响几种信号转导和代谢途径，其失调可能参与肺癌的诱导。
