Poster Presentation 31st Lorne Cancer Conference 2019

Using peptide inhibitors to target HSF1 as a novel strategy in cancer metastasis treatment  (#350)

Joe Polidano 1 , Jackie A Wilce 2 , John T Price 1 2 3
  1. Faculty of Medicine Dentistry and Health Sciences (FMDHS), University of Melbourne, Melbourne, VIC, Australia
  2. Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
  3. Institute of Sport and Health, Victoria University, Footscray, VIC, Australia

Heat Shock Factor 1 (HSF1) is the master stress transcription factor which enables cells to overcome and survive otherwise lethal stresses (heat, acidosis, hypoxia, genomic stress, oxidative stress, etc.) [1-3]. While central to several pathophysiological conditions, in cancer cells, HSF1 is intimately linked with cancer initiation, progression and metastasis [2, 4, 5]. Consistent with major involvement in metastasis, HSF1 is highly expressed and activated in high grade primary cancers, significantly increased in metastatic lesions and strongly associated with poor outcomes in cancer patients (lung, breast, prostate, etc) [6-8].  

While HSF1 has been demonstrated to be dispensable for normal function and survival (in both cell and whole animal models), in advanced cancer cells HSF1 knockdown induces lethality [4, 9]. HSF1 has consequently emerged as a major therapeutic target, and this has motivated numerous research groups to undertake programs which seek to develop HSF1 inhibitors [2, 10, 11]. However, to this end these have been unsuccessful due to an inability to specifically and directly target HSF1 (thus resulting in non-specific modes of action) [2, 10, 11]. We have taken an alternative approach to targeting HSF1, through the development of rationally designed peptide inhibitors.

In this study, we have confirmed that our peptide inhibitor (HiPe4) directly binds HSF1 through use of a biotinylated pulldown of recombinant HSF1. We have also demonstrated that the HiPe4 (through incorporation of cell permeability sequences) reduces levels of cell motility proteins and proteins directly regulated by HSF1. Importantly, other proteins not under direct HSF1 regulation have been shown to be unaffected by HiPe4.

The outcomes of this work provide essential preliminary data establishing the efficacy of HiPe4 for interacting with HSF1 and inhibiting its function in vitro, prior to further investigations we will conduct in vivo.

  1. Anckar, J. and L. Sistonen, Regulation of HSF1 function in the heat stress response: implications in aging and disease. Annu Rev Biochem, 2011. 80: p. 1089-115
  2. Dai, C. and S.B. Sampson, HSF1: Guardian of Proteostasis in Cancer. Trends Cell Biol, 2016. 26(1): p. 17-28.
  3. Vihervaara, A. and L. Sistonen, HSF1 at a glance. J Cell Sci, 2014. 127(Pt 2): p. 261-6.
  4. Dai, C., et al., Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell, 2007. 130(6): p. 1005-18.
  5. Fang, F., R. Chang, and L. Yang, Heat shock factor 1 promotes invasion and metastasis of hepatocellular carcinoma in vitro and in vivo. Cancer, 2012. 118(7): p. 1782-94.
  6. Mendillo, M.L., et al., HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers. Cell, 2012. 150(3): p. 549-562.
  7. Santagata, S., et al., High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 2011. 108(45): p. 18378-18383.
  8. Wirth, D., et al., Use of Hsf1−/− mice reveals an essential role for HSF1 to protect lung against cadmium-induced injury. Toxicology and Applied Pharmacology, 2003. 192(1): p. 12-20.
  9. Santagata, S., et al., Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state. Science, 2013. 341(6143): p. 1238303.
  10. Whitesell, L. and S. Lindquist, Inhibiting the transcription factor HSF1 as an anticancer strategy. Expert Opin Ther Targets, 2009. 13(4): p. 469-78.
  11. McConnell, J.R., L.K. Buckton, and S.R. McAlpine, Regulating the master regulator: Controlling heat shock factor 1 as a chemotherapy approach. Bioorg Med Chem Lett, 2015. 25(17): p. 3409-14.