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Modulator of the PI3K/Akt oncogenic pathway affects mTOR complex 2 in human adenocarcinoma cells

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Chaetoglobosin 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 also 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 pathway (RTK/PI3K/mTORC2/Akt) to the centrally located protein kinase, Akt. Studies have reported that ChK does not inhibit PI3K comparable to wortmannin and does not affect PDK1 activation. PDK1 is responsible for phosphorylation on Akt T308, while mTORC2 phosphorylates Akt S473. Yet, Akt’s two activation sites, T308 and S473, are known to be affected by ChK treatment. It was our hypothesis that ChK acts on the mTORC2 complex to inhibit the phosphorylation seen at Akt S473. This inhibition at mTORC2 should decrease phosphorylation at both these proteins, Akt and mTORC2 complex, compared to a known mTOR specific inhibitor, Torin1. Human lung adenocarcinoma H1299 and H2009 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.

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This work was supported by the Mercer University College of Pharmacy.

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  1. College of Pharmacy, Mercer University, 3001 Mercer University Drive, Atlanta, GA, 30341, USA

    Blair P. Curless, Nne E. Uko & Diane F. Matesic

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  1. Blair P. Curless
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Correspondence to Blair P. Curless.

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Blair P Curless declares that he has no conflict of interest. Nne E Uko declares that she has no conflict of interest. Diane F Matesic declares that she has no conflict of interest.

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Curless, B.P., Uko, N.E. & Matesic, D.F. Modulator of the PI3K/Akt oncogenic pathway affects mTOR complex 2 in human adenocarcinoma cells. Invest New Drugs 37, 902–911 (2019). https://doi.org/10.1007/s10637-018-0705-7

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