Abstract
Cisplatin is a well-known cancer chemotherapeutic agent but how extensively long non-coding RNA (lncRNA) expression is modulated by cisplatin is unknown. It is imperative to employ a comprehensive approach to obtain a better account of cisplatin-mediated changes in the expression of lncRNAs. In this study, we used a transcriptomics approach to profile lncRNAs in cisplatin-treated HeLa cells, which resulted in identification of 10,214 differentially expressed lncRNAs, of which 2,500 were antisense lncRNAs. For functional analyses, we knocked down one of the cisplatin inducible lncRNAs, death receptor 5 antisense (DR5-AS) lncRNA, which resulted in a morphological change in HeLa cell shape without inducing any cell death. A second round of transcriptomics-based profiling revealed differential expression of genes associated with immune system, motility and cell cycle in DR5-AS knockdown HeLa cells. Cellular analyses showed that DR5-AS reduced cell proliferation and caused a cell cycle arrest at S and G2/M phases. Moreover, DR5-AS knockdown reduced the invasive capacity of HeLa cells in zebrafish xenograft model. These results suggest that cisplatin-mediated pleiotropic effects, such as reduction in cell proliferation, metastasis and cell cycle arrest, may be mediated by lncRNAs.
Highlights
Cisplatin, a universal chemotherapeutic drug, is used in the treatment of a diverse array of cancer (Kelland, 2007)
Since there appears to be a correlation between the subcellular location of an long non-coding RNA (lncRNA) and its regulatory function (Carlevaro-Fita and Johnson, 2019), we examined the intracellular distribution of this transcript
We provide the first comprehensive expression profile of lncRNAs in cisplatin-treated HeLa cells
Summary
A universal chemotherapeutic drug, is used in the treatment of a diverse array of cancer (Kelland, 2007). As an alkylating-like agent, the platinum atom of cisplatin interacts with purines in DNA and induces crosslinks that lead to DNA damage and cell cycle arrest (Siddik, 2003). Such cellular perturbations trigger numerous signal transduction pathways and inflammatory pathways that trigger apoptosis. This DNA-damage-induced cell death is exploited in combination chemotherapies due to its synergistic effect. Cisplatin-Mediated Changes in lncRNA Expression important to unravel the molecular mechanisms underlying the mode of action of platinum-based chemotherapeutic drugs. Transcriptomics analysis of DR5-AS-knockdown cells has revealed that DR5AS modulates cell cycle, proliferation and metastasis without affecting cell death
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