miR4673 improves fitness profile of neoplastic cells by induction of autophagy

被引：14

作者：

Dokumcu, Kagan ^{[1
,2
,3
]}

Simonian, Mary ^{[1
,2
]}

Farahani, Ramin M. ^{[1
,2
,3
]}

机构：

[1] Westmead Inst Med Res, Inst Dent Res, Westmead, NSW, Australia

[2] Westmead Ctr Oral Hlth, Westmead, NSW, Australia

[3] Univ Sydney, Fac Med & Hlth, Dent Sch, Dept Life Sci, Sydney, NSW 2006, Australia

来源：

CELL DEATH & DISEASE | 2018年 / 9卷

关键词：

DEPENDENT PROTEIN-KINASE; ENDOPLASMIC-RETICULUM STRESS; MONOCLONAL-ANTIBODY KI-67; HOMOLOGOUS RECOMBINATION; IONIZING-RADIATION; BREAST-CANCER; NUCLEAR ANTIGEN; NOTCH PATHWAY; BETA-CATENIN; PHOSPHORYLATION;

D O I：

10.1038/s41419-018-1088-6

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Therapeutic resistance of neoplasms is mainly attributed to gradual evolution of mutational profile(1). 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(2,3). 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 nonencoded neoplastic resistance, arising as a consequence of miRNA-mediated autophagic reprogramming that uncouples phenotype and genotype.

引用

页数：17

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