Dual Inhibition of PI3K/Akt/mTOR Signaling Pathway in Leukemic Cell Lines Upregulates Long Non-Coding RNAs RNCR3, UCA1 and HULC

Decades of comprehensive research have resulted in a better understanding of the crucial role of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin signaling in different types of leukemia whereby it strongly influences the growth and survival of cancerous cells. Recently, small-molecule inhibitors have been introduced as targeted therapies that are more tolerable than conventional antineoplastic drugs for leukemia. The growth inhibition assays were performed to assess the effectiveness of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin pathway inhibitors like everolimus, torkinib and phosphokinase inhibitor 402 in leukemia cell lines. The cell cycle profiles, protein kinase B and S6 phosphorylations were assessed by flow cytometry. We also screened the expression of 96 cancer-associated long non-coding RNAs upon phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin pathway inhibition. Compared to untreated cells, the smallmolecule inhibitors treated cells showed reduced viability. Phosphokinase inhibitor 402, a dual pathway inhibitor was most effective in all cell lines (56.6 %, 32.5 % and 11.4 % in Jurkat, HL-60 and K562 cells, respectively). In addition, treatment with this resulted to shift the cells to the G1 phase from the S1 phase (Jurkat, G1: 12.2 %, S1: 4.9 %; HL-60, G1: 38.4 %, S1: 44.4 %; K562 G1: 14.4 %, S1: 15.7 %), more effectively than everolimus or torkinib. It was observed that when this inhibitor was used, the long non-coding RNAs retinal non-coding RNA 3 (3-fold) and highly up-regulated in liver cancer (2-fold) levels were significantly elevated whereas antisense non-coding ribonucleic acid in the INK4 locus and zinc finger homeobox 2 were significantly decreased by at least 25 %. Our findings revealed that dualspecificity inhibitors are more potent than single-specificity inhibitors. Hence, dual-targeted therapy may be a promising therapeutic option for leukemia. In addition, long non-coding RNAs may play a key role in drug resistance and could be a potential novel therapeutic target.