Mehmetoglu-Gurbuz Tugba, Lakshmanaswamy Rajkumar, Perez Karla, Sandoval Mayra, Jimenez Casandra A, Rocha Jackelyn, Goldfarb Rachel Madeline, Perry Courtney, Bencomo Alejandra, Neela Nishkala, Barragan Jose A, Sanchez Raquel, Swain Risa Mia, Subramani Ramadevi
Center of Emphasis in Cancer Research, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA.
Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA.
Antioxidants (Basel). 2023 Sep 22;12(10):1791. doi: 10.3390/antiox12101791.
Reactive oxygen species are frequently associated with various cancers including pancreatic ductal adenocarcinomas (PDACs). Superoxide dismutase 2 (SOD2) is an enzyme that plays an important role in reactive oxygen species (ROS) signaling. Investigating the molecular function and biological functions of SOD2 can help us develop new therapeutic options and uncover new biomarkers for PDAC diagnosis and prognosis. Here, we show that nimbolide (NB), a triterpene limonoid, effectively blocks the growth and metastasis of PDACs by suppressing the expression and activity of SOD2. To identify the role of SOD2 in NB-induced anticancer activity, we used RNA interference to silence and plasmid transfection to overexpress it. Silencing SOD2 significantly reduced the growth and metastatic characteristics like epithelial-to-mesenchymal transition, invasion, migration, and colony-forming capabilities of PDACs, and NB treatment further reduced these characteristics. Conversely, the overexpression of SOD2 enhanced these metastatic characteristics. ROS signaling has a strong feedback mechanism with the PI3K/Akt signaling pathway, which could be mediated through SOD2. Finally, NB treatment to SOD2-overexpressing PDAC xenografts resulted in significant inhibition of tumor growth and metastasis. Overall, this work suggests that NB, a natural and safe phytochemical that silences SOD2 to induce high levels of ROS generation, results in increased apoptosis and reduced growth and progression of PDACs. The role of SOD2 in regulating NB-induced ROS generation presents itself as a therapeutic option for PDACs.
活性氧物质常与包括胰腺导管腺癌（PDAC）在内的多种癌症相关。超氧化物歧化酶2（SOD2）是一种在活性氧物质（ROS）信号传导中起重要作用的酶。研究SOD2的分子功能和生物学功能有助于我们开发新的治疗方案，并发现用于PDAC诊断和预后的新生物标志物。在此，我们表明，一种三萜类柠檬苦素——印楝素（NB），通过抑制SOD2的表达和活性，有效阻断了PDAC的生长和转移。为了确定SOD2在NB诱导的抗癌活性中的作用，我们使用RNA干扰使其沉默，并通过质粒转染使其过表达。沉默SOD2显著降低了PDAC的生长和转移特性，如上皮-间质转化、侵袭、迁移和集落形成能力，而NB处理进一步降低了这些特性。相反，SOD2的过表达增强了这些转移特性。ROS信号与PI3K/Akt信号通路有强大的反馈机制，这可能通过SOD2介导。最后，对过表达SOD2的PDAC异种移植瘤进行NB处理，导致肿瘤生长和转移受到显著抑制。总体而言，这项研究表明，NB是一种天然且安全的植物化学物质，它使SOD2沉默以诱导高水平的ROS生成，从而导致PDAC的凋亡增加以及生长和进展减缓。SOD2在调节NB诱导的ROS生成中的作用为PDAC提供了一种治疗选择。
