Mazzio Elizabeth A, Lewis Charles A, Soliman Karam F A
College of Pharmacy & Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL, U.S.A.
Cancer Genomics Proteomics. 2017 Nov-Dec;14(6):409-425. doi: 10.21873/cgp.20051.
BACKGROUND/AIM: Triple-negative breast cancer (TNBC) is characterized by the absence of hormone receptors (estrogen, progesterone and human epidermal growth factor receptor-2) and a relatively poor prognosis due to inefficacy of hormone receptor-based chemotherapies. It is imperative that we continue to explore natural products with potential to impede growth and metastasis of TNBC. In this study, we screened over 1,000 natural products for capacity to induce cell death in TNBC (MDA-MB -231) cells.
Frankincense (Boswellia serrata extract (BSE)) and 3-O-Acetyl-β-boswellic acid (3-OAβBA) were relatively potent, findings that corroborate the body of existing literature. The effects of BSE and 3-OAβBA on genetic parameters in MDA-MB-231 cells were evaluated by examining whole-transcriptomic influence on mRNAs, long intergenic non-coding RNA transcripts (lincRNA) and non-coding miRNAs.
Bio-statistical analysis demarcates the primary effect of both BSE/3-OAβBA on the up-regulation of PERK (protein kinase RNA-like endoplasmic reticulum kinase)- endoplasmic reticulum (ER)/unfolded protein response (UPR) pathways that are closely tied to activated programmed cell death (APCD). Global profiling confirms concomitant effects of BSE/3-OAβBA on upwardly expressed ER/URP APCD key components PERK (EIF2AK3), XBP1, C/EBP homologous protein transcription factor (CHOP), ATF3 and DDIT3,4/DNA-damage-inducible transcript 3,4 (GADD34). Further, BSE and/or 3-OAβBA significantly down-regulated oncogenes (OG) which, heretofore, lack functional pathway mapping, but are capable of driving epithelial-mesenchymal transition (EMT), cell survival, proliferation, metastasis and drug resistance. Among these are cell migration-inducing protein hyaluronan binding (CEMIP) [-7.22]; transglutaminase 2 [-4.96], SRY box 9 (SOX9) [-4.09], inhibitor of DNA binding 1, dominant negative helix-loop-helix protein (ID1) [-6.56]; and endothelin 1 (EDN1, [-5.06]). Likewise, in the opposite manner, BSE and/or 3-OAβBA induced the robust overexpression of tumor suppressor genes (TSGs), including: glutathione-depleting ChaC glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) [+21.67]; the mTOR inhibitors - sestrin 2 (SESN2) [+16.4] Tribbles homolog 3 (TRIB3) [+6.2], homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1 (HERPUD1) [+12.01]; and cystathionine gamma-lyase (CTH) [+11.12].
The anti-cancer effects of the historically used frankincense sap (BSE) appear to involve major impact on the ER/UPR response, concomitant to effecting multiple targets counter to the growth, proliferation and metastasis of TNBC cancer cells. The microarray data are available at Expression Omnibus GEO Series accession number GSE102891.
背景/目的：三阴性乳腺癌（TNBC）的特征是缺乏激素受体（雌激素、孕激素和人表皮生长因子受体2），并且由于基于激素受体的化疗无效，其预后相对较差。我们必须继续探索具有抑制TNBC生长和转移潜力的天然产物。在本研究中，我们筛选了1000多种天然产物，以检测它们在TNBC（MDA-MB -231）细胞中诱导细胞死亡的能力。
乳香（乳香提取物（BSE））和3-O-乙酰-β-乳香酸（3-OAβBA）的作用相对较强，这一结果证实了现有文献的观点。通过检测对mRNA、长链基因间非编码RNA转录本（lincRNA）和非编码miRNA的全转录组影响，评估了BSE和3-OAβBA对MDA-MB-231细胞遗传参数的影响。
生物统计学分析表明，BSE/3-OAβBA的主要作用是上调与激活的程序性细胞死亡（APCD）密切相关的PERK（蛋白激酶RNA样内质网激酶）-内质网（ER）/未折叠蛋白反应（UPR）途径。全局分析证实了BSE/3-OAβBA对上调表达的ER/URP APCD关键成分PERK（EIF2AK3）、XBP1、C/EBP同源蛋白转录因子（CHOP）、ATF3和DDIT3,4/DNA损伤诱导转录本3,4（GADD34）的协同作用。此外，BSE和/或3-OAβBA显著下调了癌基因（OG），这些癌基因此前缺乏功能途径图谱，但能够驱动上皮-间质转化（EMT）、细胞存活、增殖、转移和耐药。其中包括细胞迁移诱导蛋白透明质酸结合蛋白（CEMIP）[-7.22]；转谷氨酰胺酶2 [-4.96]，SRY盒9（SOX9）[-4.09]，DNA结合抑制因子1，显性负性螺旋-环-螺旋蛋白（ID1）[-6.56]；以及内皮素1（EDN-1，[-5.06]）。同样，以相反的方式，BSE和/或3-OAβBA诱导了肿瘤抑制基因（TSG）的强烈过表达，包括：谷胱甘肽消耗性ChaC谷胱甘肽特异性γ-谷氨酰环转移酶1（CHAC1）[+21.67]；mTOR抑制剂- sestrin 2（SESN2）[+16.4] Tribbles同源物3（TRIB-3）[+6.2]，同型半胱氨酸诱导、内质网应激诱导、泛素样结构域成员1（HERPUD1）[+12.01]；以及胱硫醚γ-裂合酶（CTH）[+11.12]。
历史上使用的乳香汁液（BSE）的抗癌作用似乎主要涉及对ER/UPR反应的影响，同时影响多个与TNBC癌细胞生长、增殖和转移相反的靶点。微阵列数据可在基因表达综合数据库GEO系列登录号GSE102891中获取。
