Integrated molecular signaling involving mitochondrial dysfunction and alteration of cell metabolism induced by tyrosine kinase inhibitors in cancer

Abstract

Cancer cells have unlimited replicative potential, insensitivity to growth-inhibitory signals, evasion of apoptosis, cellular stress, and sustained angiogenesis, invasiveness and metastatic potential. Cancer cells adequately adapt cell metabolism and integrate several intracellular and redox signaling to promote cell survival in an inflammatory and hypoxic microenvironment in order to maintain/expand tumor phenotype. The administration of tyrosine kinase inhibitor (TKI) constitutes the recommended therapeutic strategy in different malignancies at advanced stages. There are important interrelationships between cell stress, redox status, mitochondrial function, metabolism and cellular signaling pathways leading to cell survival/death. The induction of apoptosis and cell cycle arrest widely related to the antitumoral properties of TKIs result from tightly controlled events involving different cellular compartments and signaling pathways. The aim of the present review is to update the most relevant studies dealing with the impact of TKI treatment on cell function. The induction of endoplasmic reticulum (ER) stress and Ca²⁺ disturbances, leading to alteration of mitochondrial function, redox status and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) signaling pathways that involve cell metabolism reprogramming in cancer cells will be covered. Emphasis will be given to studies that identify key components of the integrated molecular pattern including receptor tyrosine kinase (RTK) downstream signaling, cell death and mitochondria-related events that appear to be involved in the resistance of cancer cells to TKI treatments.

Keywords: Autophagy; Cell death; Endoplasmic reticulum stress; PGC-1α; Redox status; mTOR.

Fig. 1

Schematic representation of ER stress induction and downstream signaling events. Several factors might activate ER sensor chaperones inositol-requiring enzyme-1α (IRE1α), ATF6 and/or protein kinase RNA-like endoplasmic reticulum kinase (PERK), resulting in the inhibition of translation and induction of ER stress pathways. EIF2α: Eukaryotic initiation factor 2α, XBP-1: X-Box Binding Protein 1; CHOP: C/EBP homologous protein.

Fig. 2

Induction of mitochondrial dysfunction and reactive oxygen species (ROS) production by tyrosine kinase inhibitors (TKIs). TKIs act at the receptor tyrosine kinase (RTK), preventing Ras downstream events such as activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) (MEK) and ERK phosphorylation that leads reduction of angiogenesis and tumor progression. TKIs might also induce mitochondrial dysfunction. Regorafenib impairs the activity of complex I of the respiratory chain. Dasatinib inhibits complexes IV and V. Sorafenib was demonstrated to behave as a mitochondrial uncoupler, and inhibits complexes I, III, V. The resulting ROS and products of the oxidative stress might be the cause and/or consequence of the mitochondrial dysfunction. Scheme extracted from elsewhere (190).

Fig. 3

Redox regulation by tyrosine kinase inhibitors (TKIs). Two receptor tyrosine kinase (RTK) are drawn inserted in the cell membrane with their respective bound ligands. The phosphorylated Tyr (pY) sites are also shown in RTK including redox sensitive intermediates (C_SH, redox sensitive Cys in reduced state). The pathways inhibited by TKI are indicated with a red crossed line. Reactive oxygen species (ROS) generation by NADPH oxidase (NOX) and mitochondria impacts on redox sensitive sites in different targets showed with straight grey arrows. Transition from TKI-induced inhibition of cell proliferation and differentiation to resistance to TKI is indicated by a curly grey arrow and doted blue line. Events that accompany TKI resistance are displayed with vertical fine red arrows showing increased levels of nuclear transcription factor erythroid 2-related factor 2 (Nrf2)-dependent rise of antioxidant status, NOX and ROS, and activation of phosphatidylinositol 3-kinase (PI3K)/protein Kinase B (Akt) (green triangle inside a green circle). Grey arrows indicate an action. The lower part of the illustration reflects the contention that a combination of TKI treatment and down-regulation of antioxidant systems could counteract the development of TKI resistance in cancer cells (blue arrows). Janus kinase, JAK. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 4

Regulation of AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) during the treatment with tyrosine kinase inhibitors (TKIs). Regulation of cell proliferation, differentiation, angiogenesis and tumorigenesis signaling pathways by TKIs are closely related to the regulation of AMPK and mTOR. The binding of a mitogen to a receptor tyrosine kinase (RTK) stimulates the Ras/Raf/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) (MEK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling that target mTOR pathways. Among other downstream events, mTOR phosphorylates Unc51-like kinase (ULK) and inhibits autophagy. Akt negatively regulates AMPK, a protein involved in mTOR inhibition and ULK phosphorylation that promotes autophagy. Different TKIs are able to activate (green line) or inhibit (red line) specific pathways involved in downregulation of survival pathways. The activation of AMPK and inhibition of mTOR by TKIs induce autophagy and/or apoptosis that leads to the blockage of tumorigenesis and cell proliferation processes. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 5

Metabolic impact of tyrosine kinase inhibitor (TKI) administration. The inhibition of different receptor tyrosine kinase (RTK) alters all cancer hallmarks. Dovitinib, Imatinib, Gefitinib, Erlotinib and Capmatinib reduce glycolytic pathway, while Sorafenib promoted mitochondrial dysfunction. Lipid synthesis and protein synthesis were profoundly altered by TKIs. ETC; Electron transport chain.

Fig. 6

Graphical Abstract. Tyrosine kinase inhibitor (TKI) induced endoplasmic reticulum (ER) stress promoting unfolded protein response (UPR), Ca²⁺ release, translation blockage, autophagy and apoptosis. Furthermore, other mechanisms of TKIs involve mitochondrial dysfunction, generation of reactive oxygen species (ROS), AMP-activated protein kinase (AMPK) activation and mammalian target of rapamycin (mTOR) inhibition. These cellular pathways are interconnected and result in the induction of autophagy and apoptosis.