Targeting autophagy to overcome drug resistance: further developments
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REVIEW
Targeting autophagy to overcome drug resistance: further developments Haocai Chang1,2 and Zhengzhi Zou1,2*
Abstract Inhibiting cell survival and inducing cell death are the main approaches of tumor therapy. Autophagy plays an important role on intracellular metabolic homeostasis by eliminating dysfunctional or unnecessary proteins and damaged or aged cellular organelles to recycle their constituent metabolites that enable the maintenance of cell survival and genetic stability and even promotes the drug resistance, which severely limits the efficacy of chemotherapeutic drugs. Currently, targeting autophagy has a seemingly contradictory effect to suppress and promote tumor survival, which makes the effect of targeting autophagy on drug resistance more confusing and fuzzier. In the review, we summarize the regulation of autophagy by emerging ways, the action of targeting autophagy on drug resistance and some of the new therapeutic approaches to treat tumor drug resistance by interfering with autophagy-related pathways. The full-scale understanding of the tumor-associated signaling pathways and physiological functions of autophagy will hopefully open new possibilities for the treatment of tumor drug resistance and the improvement in clinical outcomes. Keywords: Autophagy, Drug resistance, Metabolic stress, p53, MAPK, miRNA, Therapeutic antibody, Histone deacetylase Introduction Autophagy is a process of self-digestion with highly conservative attributes from yeast to mammals during evolution, which allows cells to sequester cytoplasmic components and fuse with lysosomes for degradation to maintain cellular biosynthesis and energy demand during nutrient deprivation or metabolic stress. In the mammalian cells, the three best-characterized pathways of autophagy are chaperone-mediated autophagy, microautophagy and macroautophagy. The degradation process of chaperone-mediated autophagy is selective to erase the cytoplasmic proteins relying on the recognition by the heat shock cognate 70 (HSC70) chaperone with the recognizable peptide sequence motif (KFERQ) *Correspondence: [email protected] 2 Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Tianhe District, 55 Zhongshan Avenue West, Guangzhou 510631, China Full list of author information is available at the end of the article
[1]. Microautophagy directly sequesters the degradation of proteins which are translocated into the lumen in the form of lysosomal membrane invaginations [2]. Macroautophagy sequesters the cytoplasmic proteins or organelles by the expanding phagophore, leading to the formation of the double-membrane autophagosomes, which subsequently fuse with lysosomes [3]. Macroautophagy, referred to as autophagy, is closely related to the occurrence and drug resistance of tumor and chosen to be discussed in the review. Extensive studies have revealed that various signaling pathways regulate the phenomenon of autophagy. The PI3K/AKT/mTOR, LKB1/AMPK and Beclin1 complex ar
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