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dc.contributor.authorCurless, Blair P.
dc.contributor.otherMercer University. College of Pharmacy, degree granting institution.
dc.date.accessioned2018-05-31T17:51:15Z
dc.date.available2018-05-31T17:51:15Z
dc.date.copyright2018
dc.identifier.urihttp://hdl.handle.net/10898/5134
dc.description.abstractChaetoglobosin K (ChK) is a natural product that has been shown to promote F-actin capping, inhibit growth, arrest cell cycle G2 phase, and induce apoptosis. ChK has been shown to downregulate two important kinases involved in oncogenic pathways, Akt and JNK. This report investigates how ChK is involved in the receptor tyrosine kinase (RTK) pathway (RTK/PI3K/mTORC2/Akt) to the centrally located protein kinase, Akt. Akt’s two activation sites, T308 and S473, are known to be affected by ChK treatment. Studies have reported that ChK does not inhibit PI3K, unlike wortmannin, and does not affect PDK1 activation. PDK1 is responsible for phosphorylation on Akt T308, while mTORC2 phosphorylates Akt S473. It was my hypothesis that ChK acts on the mTORC2 complex to inhibit the phosphorylation seen at Akt S473. Inhibition of the mTORC2 complex would be expected to decrease phosphorylation of both Akt and mTOR in the mTORC2 complex, as observed by the known mTOR specific inhibitor, Torin1. Human lung adenocarcinoma H1299 cells were treated with IGF-1 or calyculin A to increase phosphorylation at complex mTORC2 and Akt. Pretreatment with ChK was able to significantly decrease phosphorylation at Akt S473 similarly to Torin1, with either IGF-1 or calyculin A treatment. Moreover, the autophosphorylation site on complex mTORC2, S2481, was also significantly reduced with ChK pretreatment, similar to Torin1. This is the first report to illustrate that ChK has a significant effect at mTORC2 S2481 and Akt S473 comparable to Torin1, indicating that it may be a mTOR inhibitor.
dc.format.extent87 pages.
dc.languageeng
dc.subject.lcshMercer University--Dissertations.
dc.subject.lcshLungs--Cancer--Treatment.
dc.titleDual modulator of the Akt and JNK pathways targets mTOR in human adenocarcinoma cells / by Blair P. Curless.
dc.date.updated2018-04-24T16:03:18Z
dc.language.rfc3066en


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