E-Poster Presentation 33rd Lorne Cancer Conference 2021

Secretory profiling identifies guggulsterone mediated down-regulation of VEGF, IL6 and MMP9 in breast cancer cells (#147)

Anjana Anand 1 , Javeria Haroon 1 , Lubna Therachiyil 1 2 , Rari Leo 3 , Fouad Azizi 3 , Varghese P Inchakalody 4 , Joerg Buddenkotte 3 5 , Martin Steinhoff 3 5 6 7 8 , Roopesh Krishnankutty* 1
  1. Proteomics Core Facility, Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha , 3050, Qatar
  2. Department of Pharmaceutical Sciences, College of Pharmacy, Qatar University, Doha, 2713, Qatar
  3. Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha , 3050, Qatar
  4. Translational Cancer Research Facility, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, 3050, Qatar
  5. Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, 3050, Qatar
  6. Department of Medicine , Weill Cornell Medicine-Qatar, Qatar Foundation, Doha, 24144, Qatar
  7. Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
  8. College of Medicine, Qatar University, Doha, 2713, Qatar

Background: Cancer is a devastating disease of which breast cancer is the most frequently diagnosed malignancy accountable for most cancer-related deaths in women worldwide. At the molecular level it is a heterogenic disease with treatment strategies differing according to molecular subtype and demands the need of improved systemic therapy approaches for better management. Guggulsterone (GS) [4, 17(20)-pregnadiene-3, 16-dione] a plant sterol extracted from the gum resin of tree Commiphora mukul has been renowned for its anticancer properties. The current study was aimed at identifying the efficacy of guggulsterone in modulating the expression of secretory factors in breast cancer (luminal- vs. mesenchymal-like) cells.Methods: The human derived breast cancer cells MCF-7 (luminal-like) and MDA-MB-231 (mesenchymal-like, triple-negative) were cultured using DMEM media and treated with the drug guggulsterone at defined concentration and time period. For secretory profiling, the culture supernatant was harvested and analyzed using antibody arrays (chemokine XL array) while, the cell pellets were lysed in cold RIPA buffer to obtain the protein lysates. Immunoblotting was performed by simple western system (automated western blots, Jess, Protein Simple).Results: Guggulsterone significantly inhibited the growth of breast cancer cells which was dose and time dependent. With guggulsterone treatment, about fourteen different cytokines were found to be down-regulated in their expression in MCF-7 cells while in MDA-MB-231 it accounted to fifteen. Interestingly, the angiogenic factor VEGF, the pro-inflammatory cytokine IL-6 and the protease MMP9 were observed to be significantly down-regulated (>2 fold) in both the cell lines. The down-regulated secretory factors were identified to be functionally involved in angiogenesis, inflammation, migration and metastasis. The protein-protein interaction network analysis identified interactomes with enrichment of key signaling pathways in cancer including Hypoxia Inducible Factor(HIF-1) to be significantly down-regulated. Mechanistically, guggulsterone induced autophagy in breast cancer cells as evidenced by the expression of autophagy marker LC3B and repression of Atg5. Conclusion: Guggulsterone down-regulated the expression of VEGF, IL-6, MMP as well as inhibited HIF-1 expression and induced autophagy.  

  1. 1) Leo R, Therachiyil L, Siveen SK, Uddin S, Kulinski M, Buddenkotte J, Steinhoff M, Krishnankutty R*. (2019). Protein Expression Profiling Identifies Key Proteins and Pathways Involved in Growth Inhibitory Effects Exerted by Guggulsterone in Human Colorectal Cancer Cells. Cancers (Basel);11(10):1478. doi: 10.3390/cancers11101478
  2. 2) Therachiyil L, Haroon J, Sahir F, Siveen SK, Uddin S, Kulinski M, Buddenkotte J, Steinhoff M, Krishnankutty R*. (2020). Dysregulated Phosphorylation of p53, Autophagy and Stemness Attributes the Mutant p53 Harboring Colon Cancer Cells Impaired Sensitivity to Oxaliplatin. Front Oncol. 10:1744 doi: 10.3389/fonc.2020.01744