MiR4673 improves fitness profile of neoplastic cells by induction of autophagy. Issue 11 (November 2018)

• Record Type: Journal Article
• Authors: Dökümcü, Kağan; Simonian, Mary; Farahani, Ramin
• Is Part Of: Cell death and disease. Volume 9:Issue 11(2018)
• Page Start: 1
• Page End: 17
• Publication Date: 2018-11
• Subjects: Cell death -- Periodicals; Apoptosis -- Periodicals; 571.936
• DOI: 10.1038/s41419-018-1088-6
• Languages: English
• ISSNs: 2041-4889

Abstract

Abstract Therapeutic resistance of neoplasms is mainly attributed to gradual evolution of mutational profile1 . Here, we demonstrate a microRNA-mediated mechanism that effectively improves fitness of SKBR3 mammary carcinoma cells by cytoplasmic reprogramming. The reprogramming is triggered by endogenous miR4673 transcribed from notch-1 locus. The miRNA downregulates cdk-18, a cyclin-dependent kinase that regulates M-G1 transition in cycling cells2, 3 . Suppression of cdk-18 triggers mitophagy and autophagy. Due to high autophagic flux, oestrogen receptor-1+ /progesterone receptor+ /p53+ (Esr1+ /Pr+ /p53+ ) SKBR3 cells are coerced into an Esr1− /Prlow /p53− profile. Increased mitophagy in combination with proteasomal degradation of p53 transiently arrests the cycling cells at G0 and enhances radio-resistance of the SKBR3 population. These findings highlight the impact on cancer therapy of non-encoded neoplastic resistance, arising as a consequence of miRNA-mediated autophagic reprogramming that uncouples phenotype and genotype.