Dual Inhibition of PI3K/Akt/mTOR Signaling Pathway in Leukemic Cell Lines Upregulates Long Non-Coding RNAs RNCR3, UCA1 and HULC
Core Lab, King Fahd Medical Research Center, King Abdulaziz University, 1 Blood Transfusion Services, King Abdulaziz University Hospital, King Abdulaziz University, 2Department of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia, 3Department of Pharmaceutical Sciences, Texas A&M Health Science Center, Texas A&M University, College Station Texas 77843, United States of America, 4Cancer Cell Culture & Precision Oncomedicine Lab, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar 25100, Pakistan, 5Centre of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, 6Department of Biochemistry, Cancer Metabolism and Epigenetic Unit, Faculty of Science, 7Center of Innovation in Personalized Medicine, 8Cancer and Mutagenesis Unit, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah 22252, 9King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
M. Y. Saka, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia, E-mail: firstname.lastname@example.org
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.