- Title
- Targeting adaptative mechanisms to endoplasmic reticulum stress in melanoma
- Creator
- Tay, Kwang Hong
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2014
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Melanoma is a skin cancer that remains a major public health problem in Australia because of high incidence, morbidity and mortality associated with the disease. Previously, reports from our laboratory have shown that melanoma cells have largely adapted to endoplasmic reticulum (ER) stress. This adaptation is not only responsible for resistant of melanoma cells to apoptosis induced by ER stress, but also contributes to the resistance of melanoma cells to many chemotherapeutic and biological agents. Therefore, hope for a new approach in treatment of melanoma comes from identification of the mechanisms employed in induction of apoptosis by ER stress and the possible resistance mechanisms in melanoma cells against ER stress-induced apoptosis. The aim of this thesis was to further elucidate mechanisms of ER stress-induced apoptosis and interactions between ER stress pathways and other signalling pathways in melanoma, thus providing more information in identification of treatment approaches that will increase the sensitivity of melanoma to apoptosis induced by ER stress. In chapter 3, we showed that sustained activation of the IRE1α and ATF6 pathways of the UPR is critical for survival of melanoma cells undergoing prolonged ER stress. This indicates that persistent activation of the pathways is an important adaptive mechanism to ER stress in melanoma cells, and suggest that interruption of IRE1α and ATF6 signalling may be useful in combination with drugs that induce ER stress to kill melanoma cells. Moreover, the observation that the MEK/ERK pathway is required for sustained activation of IRE1α and ATF6 in melanoma cells under ER stress reinforces the importance of inhibition of the pathway in the treatment of melanoma. A characteristic of human melanoma is the constitutive activation of the MEK/ERK pathway due o activating mutations of key components of the pathway, in particular, BRAF. Studies in Chapter 4 extend the findings in Chapter 3 by showing that oncogenic activation of the MEK/ERK pathway is not only a mechanism of adaptation to ER stress, but also a source of chronic ER stress in melanoma cells. While activation of MEK/ERK is important for enabling increased protein synthesis by activation of eIF4E, it consequently causes ER stress. Nonetheless, MEK/ERK signalling potentiates IRE1α and ATF6 signalling of the UPR, which protects melanoma cells against ER stress-induced apoptosis. These results reveal that regulation of the UPR is another mechanism by which oncogenic activation of the MEK/ERK pathway promotes the pathogenesis of melanoma. Although ER stress triggers apoptosis by activating Bim in various types of cells, Bim activation is suppressed in melanoma cells undergoing ER stress. In Chapter 5, it is demonstrated that ER stress reduces PP2A activity leading to increased ERK activation and subsequent phosphorylation and proteasomal degradation of the Bim protein. The increase in ERK activation is, at least in part, due to reduced dephosphorylation by PP2A, which is associated with downregulation of the PP2A catalytic subunit. These results suggest that pharmacological activation of PP2A may improve treatment results of agents that induce ER stress in melanoma cells. Results presented in this thesis provided new insights into mechanisms involved, and suggest that targeting MEL/ERK signalling, interruption of the IRE1α and ATF6 pathways, and activations of PP2A are potentially useful strategies to improve the therapeutic efficacy of agents that inducing ER stress.
- Subject
- melanoma; ER stress; apoptosis; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1043155
- Identifier
- uon:14172
- Rights
- Copyright 2014 Kwang Hong Tay
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Abstract | 185 KB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Thesis | 9 MB | Adobe Acrobat PDF | View Details Download |