Abstract：
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.
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.
摘要：
三阴性乳腺癌（TNBC）的特征是缺乏激素受体（雌激素，孕酮和人表皮生长因子受体2）以及由于基于激素受体的化疗无效而导致的相对较差的预后。我们必须继续探索具有阻止TNBC生长和转移潜力的天然产物。在这项研究中,我们筛选了超过1,000种天然产物在TNBC（MDA-MB-231）细胞中诱导细胞死亡的能力。
乳香（Boswelliaserrata提取物（BSE））和3-O-乙酰-β-乳香酸（3-OAβBA）相对有效，证实现有文献主体的发现。BSE和3-OAβBA对MDA-MB-231细胞遗传参数的影响通过检测对mRNAs的全转录组影响来评估。长基因间非编码RNA转录本(lincRNA)和非编码miRNA。
生物统计分析界定了BSE/3-OAβBA对PERK（蛋白激酶RNA样内质网激酶）-内质网（ER）/未折叠蛋白反应（UPR）途径上调的主要作用，这些途径与活化的程序性细胞死亡（APCD）密切相关。全局分析证实了BSE/3-OAβBA对上调表达的ER/URPAPCD关键成分PERK（EIF2AK3）的伴随作用，XBP1,C/EBP同源蛋白转录因子(CHOP),ATF3和DDIT3,4/DNA损伤诱导型转录物3,4(GADD34)。Further,BSE和/或3-OAβBA显著下调癌基因(OG)，到目前为止，缺乏功能通路映射，但能够驱动上皮-间质转化（EMT），细胞存活,扩散,转移和耐药性。其中包括细胞迁移诱导蛋白透明质酸结合（CEMIP）[-7.22];转谷氨酰胺酶2[-4.96]，SRY箱9(SOX9)[-4.09],DNA结合抑制剂1，显性负螺旋-环-螺旋蛋白（ID1）[-6.56]；和内皮素1（EDN1，[-5.06]）。同样，以相反的方式，BSE和/或3-OAβBA诱导肿瘤抑制基因（TSG）的强烈过表达，包括:谷胱甘肽消耗ChaC谷胱甘肽特异性γ-谷氨酰环基转移酶1(CHAC1)[+21.67];mTOR抑制剂-setrin2(SESN2)[+16.4]Tribbbles同源物3(TRIB3)[+6.2],同型半胱氨酸诱导型,内质网应激诱导,泛素样结构域成员1(HERPUD1)[+12.01];和胱硫醚γ-裂解酶(CTH)[+11.12]。
历史上使用的乳香汁（BSE）的抗癌作用似乎涉及对ER/UPR反应的重大影响，伴随着实现与增长相反的多个目标，TNBC癌细胞的增殖和转移。微阵列数据可从表达OmnibusGEO系列登录号GSE102891获得。
乳香（Boswelliaserrata提取物（BSE））和3-O-乙酰-β-乳香酸（3-OAβBA）相对有效，证实现有文献主体的发现。BSE和3-OAβBA对MDA-MB-231细胞遗传参数的影响通过检测对mRNAs的全转录组影响来评估。长基因间非编码RNA转录本(lincRNA)和非编码miRNA。
生物统计分析界定了BSE/3-OAβBA对PERK（蛋白激酶RNA样内质网激酶）-内质网（ER）/未折叠蛋白反应（UPR）途径上调的主要作用，这些途径与活化的程序性细胞死亡（APCD）密切相关。全局分析证实了BSE/3-OAβBA对上调表达的ER/URPAPCD关键成分PERK（EIF2AK3）的伴随作用，XBP1,C/EBP同源蛋白转录因子(CHOP),ATF3和DDIT3,4/DNA损伤诱导型转录物3,4(GADD34)。Further,BSE和/或3-OAβBA显著下调癌基因(OG)，到目前为止，缺乏功能通路映射，但能够驱动上皮-间质转化（EMT），细胞存活,扩散,转移和耐药性。其中包括细胞迁移诱导蛋白透明质酸结合（CEMIP）[-7.22];转谷氨酰胺酶2[-4.96]，SRY箱9(SOX9)[-4.09],DNA结合抑制剂1，显性负螺旋-环-螺旋蛋白（ID1）[-6.56]；和内皮素1（EDN1，[-5.06]）。同样，以相反的方式，BSE和/或3-OAβBA诱导肿瘤抑制基因（TSG）的强烈过表达，包括:谷胱甘肽消耗ChaC谷胱甘肽特异性γ-谷氨酰环基转移酶1(CHAC1)[+21.67];mTOR抑制剂-setrin2(SESN2)[+16.4]Tribbbles同源物3(TRIB3)[+6.2],同型半胱氨酸诱导型,内质网应激诱导,泛素样结构域成员1(HERPUD1)[+12.01];和胱硫醚γ-裂解酶(CTH)[+11.12]。
历史上使用的乳香汁（BSE）的抗癌作用似乎涉及对ER/UPR反应的重大影响，伴随着实现与增长相反的多个目标，TNBC癌细胞的增殖和转移。微阵列数据可从表达OmnibusGEO系列登录号GSE102891获得。
