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A pharmacological model reveals biased dependency on PI3K isoforms for tumor cell growth

  
@article{APS6814,
	author = {Xiang Wang and Jia-peng Li and Yan Yang and Jian Ding and Ling-hua Meng},
	title = {A pharmacological model reveals biased dependency on PI3K isoforms for tumor cell growth},
	journal = {Acta Pharmacologica Sinica},
	volume = {34},
	number = {9},
	year = {2016},
	keywords = {},
	abstract = {Aim: To identify the contribution of individual isoform (α, β, γ, δ) of class I PI3Ks to tumor cell growth for proper use of PI3K inhibitors in cancer therapy.
Methods: A panel of human rhabdomyosarcoma Rh30 cells stably expressing myristoylation (Myr)-tagged one of class I PI3K p110 subunits was established. PI3K activity was analyzed by measuring phosphorylated Akt with Western blotting, and isoform-specific PI3K activities were validated with PI3K isoform-selective inhibitors. The growth of prostate cancer PC-3 cells and B cell type leukemia Raji cells was determined using SRB assay and CCK-8 assay, respectively.
Results: The phosphorylation of Akt in Rh30-Myr-p110α, β, γ, δ cells was preferentially inhibited by PI3K isoform-selective inhibitors A66 (PI3Kα), TGX221 (PI3Kβ), AS604850 (PI3Kγ) and CAL-101 (PI3Kδ), respectively. A newly obtained PI3K inhibitor WJD008 (10 μmol/L) completely abrogated Akt phosphorylation by all the isoforms of class I PI3Ks, thus acted as a pan-PI3K inhibitor. In prostate cancer PC-3 cells, the PI3K isoform-selective inhibitors were much less potent than WJD008 in suppression of the proliferation. In B cell type leukemia Raji cells, inhibition of PI3Kδ alone or all the isoforms of class I PI3Ks displayed similar potency against the cell proliferation, whereas selective inhibition of individual PI3Kα/β/γ isoforms resulted in negligible activity.
Conclusion: Rh30-Myr-p110α, β, γ, δ cells are a useful cell model to identify the selectivity of PI3K inhibitors. Pan-PI3K inhibitors are suitable for treating PC-3 cells, whereas selective PI3Kδ inhibitor is sufficient to block Raji cell growth. The biased dependency on PI3K isoforms for tumor cell growth rationalizes the use of PI3K inhibitors with different selectivity for cancer therapy.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/6814}
}