Inhibition of the LINE1-derived transcript induces apoptosis and oncoprotein knockdown in cancer cells.

The expression of intragenic long interspersed nuclear elements 1 (LINE1s) can generate chimeric sequences disrupting host gene transcription. Among these, L1-, within () oncogene, is particularly interesting, as its expression has been associated with the acquisition of tumorigenic phenotypes and cancer progression. We investigated the effects of targeting L1- in eight cancer cell lines derived from breast, lung, and gastrointestinal cancers, as well as in non-transformed human fibroblasts and lymphocytes, using specifically developed modified antisense oligonucleotides. Inhibition of L1- resulted in decreased cell viability, increased apoptosis, and gene expression profile reprogramming in cancer cells, including significant downregulation of MET and epidermal growth factor receptor (EGFR) proteins. These effects were related to the L1- expression levels and the type of cellular addiction, with pronounced impacts in cells harboring gene amplification and activating mutations. They were also detectable, though less pronounced, in cancer cells with steady-state levels of MET and EGFR proteins or addiction to other oncogenes. We demonstrate that targeting L1- can knockdown MET and EGFR protein. The restricted expression of L1- to cancer cells suggests that its inhibition could be an effective strategy to induce death in oncogene-addicted tumor cells and offers a potential means to overcome the limitations of conventional targeted therapies.