Abstract
Overcoming drug resistance of cancer cells is the major challenge in molecular oncology. Here, we demonstrate that long non-coding RNA LINC00973 is up-regulated in normal and cancer cells of different origins upon treatment with different chemotherapeutics. Bioinformatics analysis shows that this is a consequence of DNA damage response pathway activation or mitotic arrest. Knockdown of LINC0973 decreases p21 levels, activates cellular proliferation of cancer cells, and suppresses apoptosis of drug-treated cells. We have found that LINC00973 strongly increases p21 protein content, possibly by blocking its degradation. Besides, we have found that ectopic over-expression of LINC00973 inhibits formation of the pro-survival p53-Ser15-P isoform, which preserves chromosome integrity. These results might open a new approach to the development of more efficient anti-cancer drugs.
Highlights
Investigation of molecular mechanisms, which determine the resistance of cancer cells to anticancer drugs, holds promise for the development of more efficient chemotherapeutics that inhibit both tumor progression and relapse
This results in cell cycle and translational arrest followed by apoptosis of “unrepairable” cells
Drug-resistant cancer cells treated with chemotherapeutics prevent cell cycle arrest, which is necessary for completion of DNA damage repair, and block apoptosis and autophagy [3,4]
Summary
Investigation of molecular mechanisms, which determine the resistance of cancer cells to anticancer drugs, holds promise for the development of more efficient chemotherapeutics that inhibit both tumor progression and relapse. Generated DNA lesions are detected by ATM, ATR, and DNA-PKcs protein kinases, which activate the DNA damage repair pathway (DDR) that induces phosphorylation of nearly 700 protein targets [2]. This results in cell cycle and translational arrest followed by apoptosis of “unrepairable” cells. We have discovered a significant increase in the expression of the long non-coding RNA LINC00973 in response to treatment of two colon cancer cell lines with three anticancer drugs both in vitro and in vivo [7]. Obtained results demonstrated that LINC00973 is predominantly a nuclear RNA, which inhibits proliferation of normal and cancer cells by blocking S/G2 transition, inducing apoptosis in response to anti-cancer drugs
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