Curcumin analog HO-3867 inhibited STAT3 and induced apoptosis in pancreatic cancer cell lines

 

STATs are transcription factors which are normally present in the cytoplasm and activated by inflammatory signalling associated with epithelial to mesenchymal transition (EMT) which leads to their nuclear import [1]. STAT3 expression is maintained and constitutive activation has been reported in at least 30% of pancreatic cancers [2].

 

Fatty acid synthase (FASN) is a key enzyme involved in lipogenesis and the production of long-chain fatty acids from acetyl-coenzyme A (CoA) and malonyl-CoA which is crucial for rapidly growing cancer cells including pancreatic [3]. The inhibition of fatty acid synthase is known to increase reactive oxygen species (ROS) levels in cancer which is associated with apoptosis [4].

 

Focal Adhesion Kinase (FAK) inhibitors demonstrated in preclinical pancreatic cancer models increased mouse survival time via tumour stasis, reduced collagen deposition and reduced numbers of activated fibroblasts, down-regulated gene expression of fibrosis associated markers, reduced cancer stem-like cell numbers, reduced numbers of immunosuppresive cells within tumours, synergized with gemcitabine treatment, synergized with adoptive T cell transfer to reduce tumour volume and was associated with increased numbers of therapeutic T cell in the tumour and synergised with checkpoint inhibitors under certain circumstances [5].

 

Figure 1: HO-3867 mechanisms of action in cancer cells. HO-3867 down-regulates FASN and FAK protein expression leading to apoptosis and decreased cell migration respectively. HO-3867 also inhibits STAT3 phosphorylation which leads to apoptosis and possibly decreased cell migration.

 

The curcumin analog HO-3867 has recently been shown to inhibit STAT3 and down-regulate fatty acid synthase in pancreatic cancer cells leading to apoptosis via ROS [6]. In addition in ovarian cancer models HO-3867 down-regulates FAK [7]. The potential to inhibit STAT3, FASN and FAK with a single agent is very promising and warrants further investigation as a potential therapeutic for pancreatic cancer (Figure 1).

 
Refs

 

1. Kaplan, Mark H. ‘STAT Signaling in Inflammation’. JAK-STAT 2, no. 1 (January 2013): e24198. doi:10.4161/jkst.24198.
2. Corcoran, R. B., G. Contino, V. Deshpande, A. Tzatsos, C. Conrad, C. H. Benes, D. E. Levy, J. Settleman, J. A. Engelman, and N. Bardeesy. ‘STAT3 Plays a Critical Role in KRAS-Induced Pancreatic Tumorigenesis’. Cancer Research 71, no. 14 (15 July 2011): 5020–29. doi:10.1158/0008-5472.CAN-11-0908.
3. Flavin R, Peluso S, Nguyen PL, Loda M. Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol. 2010 Apr;6(4):551-62. Doi: 10.2217/fon.10.11. Review. PubMed PMID: 20373869.
4. Zecchin KG, Rossato FA, Raposo HF, Melo DR, Alberici LC, Oliveira HC, Castilho RF, Coletta RD, Vercesi AE, Graner E. Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis. Lab Invest. 2011 Feb;91(2):232-40. doi:10.1038/labinvest.2010.157. Epub 2010 Aug 30. PubMed PMID: 20805790.
5. Jiang, Hong, Samarth Hegde, Brett L Knolhoff, Yu Zhu, John M Herndon, Melissa A Meyer, Timothy M Nywening, et al. ‘Targeting Focal Adhesion Kinase Renders Pancreatic Cancers Responsive to Checkpoint Immunotherapy’. Nature Medicine, 4 July 2016. doi:10.1038/nm.4123. PMID: 27376576.
6. Hu Y, Zhao C, Zheng H, Lu K, Shi D, Liu Z, Dai X, Zhang Y, Zhang X, Hu W, Liang G. A novel STAT3 inhibitor HO-3867 induces cell apoptosis by reactive oxygen species-dependent endoplasmic reticulum stress in human pancreatic cancer cells. Anticancer Drugs. 2017 Jan 6. doi: 10.1097/CAD.0000000000000470. PubMed PMID: 28067673.
7. Selvendiran K, Ahmed S, Dayton A, Ravi Y, Kuppusamy ML, Bratasz A, Rivera BK, Kálai T, Hideg K, Kuppusamy P. HO-3867, a synthetic compound, inhibits the migration and invasion of ovarian carcinoma cells through downregulation of fatty acid synthase and focal adhesion kinase. Mol Cancer Res. 2010 Sep;8(9):1188-97. doi: 10.1158/1541-7786.MCR-10-0201. PubMed PMID: 20713491.