Investigating HSP90 as the molecular switch for cancer cell metastasis

Taylor, Laura (2020) Investigating HSP90 as the molecular switch for cancer cell metastasis. MRes thesis, University of Lincoln.

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Investigating HSP90 as the molecular switch for cancer cell metastasis
MRes Thesis
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Abstract

Heat shock proteins (HSPs), play an essential role in housekeeping functions in the body. When these are mis-used, HSPs are thought to play a significant role in the mechanisms leading to cancer cell development, a main
aspect of this being metastasis. Metastasis is the spread of cancer cells to other areas of the body, and is often
linked to a poor prognosis for diagnosed patients. This makes metastasis a very important issue to understand,
and control. The blocking of metastasis, resulting in the tumour to stay in one tissue, provides better scope for
treatment, especially in the case of surgery. One such HSP of interest, Heat shock protein 90 (HSP90) is found
in all tissues of the body, with its cumulative expression level under non-stress conditions being very high. A
target to reduce of halt metastasis needs to be identified, this could also be used as a biochemical marker for
cancer prognosis. The aims of this study are to observe HSP90 output over time, analyse its role in cancer cell
motility, assess for the use of HSP90 as a potential biomarker for cancer prognosis, and to analyse the synergy
between HSP90 and TOR inhibitors, with the possibility of therapeutic use of dual drugging regimes.
HSP90, plays a role in many cellular processes, such as signally pathways and cell survival. Due to this, HSP90 has
been identified as a promising cancer drug target due to its critical role in stabilization and activation of several
of the oncoproteins required for driving cancer cell progression, including being implicated in metastasis. In this
investigation, wound assays were used to visualise cancer cell metastasis over time, with and without a drugging
regime. Rapamycin and 17-allylamino-17-demethoxy-geldanamycin (17-AAG) were investigated as a drugging
regime to analyse synergistic lethality as a dual treatment for cancer. Cancer cells were analysed using Western
Blot to identify presence and concentration of HSP90 in the cells, to identify the effectiveness of the drugging
regime. This resulted in the reduction of cancer cell metastasis using the optimum dosing concentration of
0.5μM Rapamycin and 5.1μM 17-AAG. The use of western blots also resulted in images demonstrating the ability
of HSP90 to be used as a biomarker for cancer prognosis. These findings are significant when considering
drugging regimes in human trails which look to reduce cancer cell metastasis, and which look to use biomarkers
to personalise treatment in future. The major findings of this study were the confirmation that HSP90 is strongly
involved in cancer cell metastasis, that its phosphorylated residues can be used as marker of cancer prognosis,
and the identification of a successful drugging regime by combining Rapamycin and 17-AAG.

Keywords:cancer, metastasis, heat shock protein
Subjects:C Biological Sciences > C100 Biology
Divisions:College of Science > School of Life Sciences
ID Code:48590
Deposited On:16 Mar 2022 15:43

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