The Chaperone TRAP1 As a Modulator of the Mitochondrial Adaptations in Cancer Cells

Abstract

Mitochondria can receive, integrate, and transmit a variety of signals to shape many biochemical activities of the cell. In the process of tumor onset and growth, mitochondria contribute to the capability of cells of escaping death insults, handling changes in ROS levels, rewiring metabolism, and reprograming gene expression. Therefore, mitochondria can tune the bioenergetic and anabolic needs of neoplastic cells in a rapid and flexible way, and these adaptations are required for cell survival and proliferation in the fluctuating environment of a rapidly growing tumor mass. The molecular bases of pro-neoplastic mitochondrial adaptations are complex and only partially understood. Recently, the mitochondrial molecular chaperone TRAP1 (tumor necrosis factor receptor associated protein 1) was identified as a key regulator of mitochondrial bioenergetics in tumor cells, with a profound impact on neoplastic growth. In this review, we analyze these findings and discuss the possibility that targeting TRAP1 constitutes a new antitumor approach.

Keywords: allosteric ligands; heat shock proteins; kinase; mitochondria; post-translational modifications; reactive oxygen species; tumor metabolism; tumor necrosis factor receptor-associated protein 1.

Figure 1

Mitochondria and cancer. Mitochondria play a crucial role in several biological routines involved in tumorigenesis (1): control of ROS levels, whose increase can lead to DNA mutations and genomic instability; autophagy regulation; resistance to cell death stimuli; metabolic changes, such as decreased oxidative phosphorylation (OXPHOS) and induction of anabolic pathways; dysregulation of transduction pathways, including kinase signaling and changes in oncometabolite levels that modulate transcription factors and epigenetic changes.

Figure 2

Schematic representation of the of the TRAP1 conformational cycle. TRAP1 protomers are shown in different hues and colored orange [ADP-bound or naked N-terminal domain (NTD)], red (ATP-bound NTD), blue [middle domain (MD)], and green [C-terminal domain (CTD)]. In the absence of bound nucleotides (apo state), TRAP1 populates a number of states with open conformations. Upon ATP binding, the chaperone shifts to an asymmetric closed conformation with significant strain, leading to buckling of the MD:CTD interface. After hydrolysis of the first ATP, strain is relieved and the MD:CTD interface is rearranged, forming a symmetric state. Hydrolysis of the second ATP leads to the formation of the ADP state. The cycle eventually returns to the open conformation after ADP release (–42).

Figure 3

TRAP1 activity in tumor cell mitochondria. (A) TRAP1 inhibits oxidative phosphorylation (OXPHOS) by interacting with both succinate dehydrogenase (SDH) and cytochrome oxidase, aka complex II and complex IV of the respiratory chain, respectively. SDH inhibition is enhanced by ERK1/2-dependent phosphorylation of TRAP1 and leads to succinate-dependent stabilization of the transcription factor HIF1α, which masters several pro-neoplastic programs (65, 69). Downregulation of cytochrome oxidase activity relies upon the inhibitory interaction between TRAP1 and Src (66). (B) TRAP1 inhibits ROS generation by SDH and cytochrome oxidase (66, 70). This, together with the interaction with other chaperones, such as cyclophilin D (CyP-D) and heat shock protein 90 (HSP90), inhibits opening of the permeability transition pore (PTP), which requires conformational changes of the ATP synthase and leads to cell death (71, 72). Therefore, TRAP1 protects tumor cells from cell death stimuli.

Figure 4

TRAP1 inhibition by small molecules. TRAP1 inhibitors can act either at the level of the ATP-binding pocket (the yellow portion of the two protomers), with the aim of blocking ATP hydrolysis, or at an allosteric druggable site, in analogy with heat shock protein 90 (101, 102). In red, it is represented a potential target of allosteric inhibitors at the middle domain:C-terminal domain interface.