The non-receptor tyrosine kinase Src has been found to be overexpressed and activated in many human cancers, where it has been implicated in changes in cellular proliferation, adhesion, migration, apoptosis, angiogenesis, and tumour growth. In addition, several other members of the Src family have also been implicated in various cancer phenotypes. Our examination of a wide panel of colon, breast, and lung cancer cell lines revealed that not only Src, but also Yes, Fyn, Lyn, and Lck, were expressed at both the mRNA and protein levels in different combinations, and at varying levels, between cell lines. When examined for kinase activity, it was discovered that only a subset of the expressed Src family members had detectable kinase activity within a given cell line. To investigate the involvement of the Src family members in the proliferation, adhesion, migration, and colony forming ability of four selected cancer cell lines, both Src family kinase inhibitors, which inhibit the kinase activity of multiple Src family members, and RNA interference, which selectively decreases the expression of individual proteins, were used. It was found that the involvement of these proteins in all of the cellular processes investigated was cell line-specific, with the greatest effects observed in HT29 cells, which have relatively high Src protein levels and kinase activity. Furthermore, the consequences of Src family member inhibition were also inhibitor specific, as treatment with PP2 and SKI I generally had greater effects on the cellular processes examined than did treatment with SU6656 or SKI II. It was also found that the inhibition of multiple Src family kinases by at least one of the inhibitors generally resulted in greater effects on the cancer cell phenotypes investigated than were observed when the expression of Src, Fyn, or Yes was decreased using RNA interference. This suggests that multiple Src family members may need to be targeted in order to inhibit the increased proliferation, cell-matrix adhesion, migration, and colony forming ability exhibited by cancer cells. The identification of the cancer cell phenotypes in which particular Src family members are involved is of interest, as these proteins are attractive targets for cancer therapy.
| Identifer | oai:union.ndltd.org:USASK/oai:usask.ca:etd-03302011-231143 |
| Date | 31 March 2011 |
| Creators | Smith-Windsor, Erin Lea |
| Contributors | Mousseau, Darrell D., Wang, Hong, Warrington, Rob C., Bonham, Keith, Fujita, Donald J., Khandelwal, Ramji L. |
| Publisher | University of Saskatchewan |
| Source Sets | University of Saskatchewan Library |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://library.usask.ca/theses/available/etd-03302011-231143/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Saskatchewan or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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