Integrated molecular signalling involving mitochondrial dysfunction and alteration of cell metabolism during antitumoral properties of 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 signalling to promote cell survival in an inflammatory and hypoxic microenvironment in order to maintain/expand tumour phenotype. Tyrosine kinase inhibitors (TKI) constitute the recommended therapeutic strategies in different malignancies at advanced stages, which critically alters the hallmarks in cancer cells. There is an important interrelationship among cell stress and redox status, mitochondrial function, metabolism, and diverse cellular signaling leading to cell survival/death. The induction of apoptosis and antiproliferative properties widely related to the antitumoral properties of the treatments result from the tightly controlled events involving different relevant cellular compartments and cell signalling. The aim of the present review is to update the most relevant studies facing the impact of TKI treatment in the induction of endoplasmic reticulum (ER) stress and Ca2+ disturbances, leading to alteration of mitochondrial function, redox status and phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR)-AMP-activated protein kinase (AMPK) signalling that involve cell metabolism reprogramming in cancer cells. These studies also identify key components of the integrated molecular signalling involving TKI receptors (TKR) downstream signalling, cell death and mitochondria-related events that appears to be involved in the resistance to TKI treatment in cancer cells.