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miR4673 improves fitness profile of neoplastic cells by induction of autophagy.

Authors :: Dökümcü K
Simonian M
Farahani RM
Source :: Cell death & disease [Cell Death Dis] 2018 Oct 19; Vol. 9 (11), pp. 1068. Date of Electronic Publication: 2018 Oct 19.
Publication Year :: 2018
Abstract: Therapeutic resistance of neoplasms is mainly attributed to gradual evolution of mutational profile <superscript>1</superscript> . 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 cells <superscript>2,3</superscript> . Suppression of cdk-18 triggers mitophagy and autophagy. Due to high autophagic flux, oestrogen receptor-1 <superscript>+</superscript> /progesterone receptor <superscript>+</superscript> /p53 <superscript>+</superscript> (Esr1 <superscript>+</superscript> /Pr <superscript>+</superscript> /p53 <superscript>+</superscript> ) SKBR3 cells are coerced into an Esr1 <superscript>-</superscript> /Pr <superscript>low</superscript> /p53 <superscript>-</superscript> 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.