Targeting autophagy to overcome drug resistance: further developments

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; Histone deacetylase; MAPK; Metabolic stress; Therapeutic antibody; miRNA; p53.

Fig. 1

Overview of the autophagy-lysosomal degradation process. The initiation of autophagy is induced by a multiprotein complex consisting of ULK1/2, FIP200, ATG13, ATG17 and ATG101, which integrates stress signals from mTOR, AMPK and MAPK. The nucleation phase is controlled by Beclin1/VPS34/UVRAG/ATG4L/Bif-1 complex, which is negatively regulated by the antiapoptotic protein Bcl-2/Bcl-XL via its BH3 domain. The ATG12/ATG5/ATG16 and LC3-II are two dominate factors in the elongation phase to drive phagophore expansion. E3 ligase-like ATG12/ATG5/ATG16 multimeric complex is formed by the interaction of those proteins under the action of ligase E1 ATG7 and ligase E2 ATG10, and mediated membrane binding. LC3-II is from a cytosolic form of LC3-I by conjugating phosphatidylethanolamine (PE), which is catalyzed by ligase E1 ATG7 and ligase E2 ATG3, and then LC3-II is inserted into both outer and inner membranes of the growing phagophore. LC3-I is derived from pro-LC3 by ATG4 proteolytic cleavage to expose a C-terminal glycine and then conjugate PE. In the docking and fusion phase, autolysosome is generated by the fusion of autophagosome and lysosome. Finally the cargo-containing membrane and cytoplasm compartments are degraded and the essential biomolecules are recycled. Autophagy attenuates the damage caused by tumor therapeutic drugs and then produces multidrug resistance (MDR)

Fig. 2

Regulation of autophagy. Multiple signaling pathways triggered by growth signals and energy status are integrated by mTOR, a core regulator of autophagic signaling, which initiate autophagy induction and inhibition. Cellular stresses, including genotoxic stress, ER stress, hypoxic stress and ROS, also elicit a series of intracellular and extracellular signal events and change the level of autophagic flux through distinct mechanisms

Fig. 3

Regulation of autophagy by ER stress. Four major signaling pathways, including IRE1α, ATF6, PERK and Ca²⁺-related pathways implicated in ER stress-triggered autophagy. Among those pathways, UPR is triggered by the activation of the above three protein sensors (IRE1α, ATF6 and PERK) and regulates the transcription of autophagy genes and/or the function of autophagy protein. The release of Ca²⁺ from ER can activate autophagy via Ca²⁺/CaMKKβ/AMPK and PKCθ pathways. Dashed arrows indicate that the effect is multistep

Fig. 4

Overview of the miRNAs and specific targets involved in the regulation of autophagy at different stages

Fig. 5

Employing autophagy against tumors. Basic autophagy recycles dysfunctional or unnecessary proteins and damaged or aged cellular organelles to provide constituent metabolites for cells, and inhibits tumorigenesis. The induction of moderate autophagy by drugs, which possess a higher autophagic flux and triggers drug resistant and even refractory cancer against the induced apoptosis, can be repressed by some chemical inhibitors or therapeutic antibodies (such as RTK inhibitors, AKT inhibitors, proteasome inhibitors, cell cycle inhibitors, miRNA, and EGFR and HER2 therapeutic antibodies). Conversely, other inhibitors (such as mTOR inhibitors, HDAC inhibitors, PARP inhibitors and Bcl-2 inhibitors) and enforced expression of ATG (such as ATG3, ATG4, ATG5, ATG9 and Beclin1) further improve autophagic flux and lead to cell autophagic death due to the excessive autophagy