Transcriptomic Profiling of MDA-MB-231 Cells Exposed to Boswellia Serrata and 3-O-Acetyl-B-Boswellic Acid; ER/UPR
Elizabeth A Mazzio1, Charles A Lewis1, Karam F A Soliman2
1College of Pharmacy & Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL, U.S.A.
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.
Materials And Methods:
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.
Results:
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].
Conclusion:
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.
Insights
Frankincense extract and its derivative 3-O-Acetyl-β-boswellic acid show potent anti-cancer effects against triple-negative breast cancer (TNBC) by inducing cell death and modulating key cancer-related genes.
Area of Science:
- Oncology
- Natural Products Chemistry
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) lacks effective targeted therapies due to absence of hormone receptors.
- Natural products offer a promising avenue for novel TNBC treatments.
- This study investigated the anti-cancer potential of frankincense extract against TNBC.
Purpose of the Study:
- To screen natural products for their ability to induce cell death in TNBC cells.
- To elucidate the molecular mechanisms underlying the anti-cancer effects of frankincense and its derivatives.
- To identify key genetic targets modulated by these natural compounds.
Main Methods:
- Screening of over 1,000 natural products against MDA-MB-231 TNBC cells.
- Evaluation of whole-transcriptomic effects of Boswellia serrata extract (BSE) and 3-O-Acetyl-β-boswellic acid (3-OAβBA) on mRNA, lincRNA, and miRNA.
- Bio-statistical analysis of gene expression changes.
Main Results:
- BSE and 3-OAβBA significantly up-regulated endoplasmic reticulum (ER)/unfolded protein response (UPR) pathways linked to programmed cell death.
- Key ER/UPR components like PERK, XBP1, CHOP, ATF3, and GADD34 were upregulated.
- BSE/3-OAβBA down-regulated oncogenes (e.g., CEMIP, SOX9, ID1) and up-regulated tumor suppressor genes (e.g., CHAC1, SESN2, TRIB3).
Conclusions:
- Frankincense sap (BSE) exhibits anti-cancer effects against TNBC by impacting the ER/UPR pathway.
- These compounds target multiple pathways crucial for TNBC growth, proliferation, and metastasis.
- Microarray data are available under GEO Series accession number GSE102891.
