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

Description

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 adaptcell metabolism and integrate several intracellular and redox signaling to promote cell survival in an in-flammatory and hypoxic microenvironment in order to maintain/expand tumor phenotype. The administrationof tyrosine kinase inhibitor (TKI) constitutes the recommended therapeutic strategy in different malignancies atadvanced stages.There are important interrelationships between cell stress, redox status, mitochondrial function, metabolismand cellular signaling pathways leading to cell survival/death. The induction of apoptosis and cell cycle arrestwidely related to the antitumoral properties of TKIs result from tightly controlled events involving differentcellular compartments and signaling pathways. The aim of the present review is to update the most relevantstudies 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 phosphatidyli-nositol 3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) and AMP-activatedprotein kinase (AMPK) signaling pathways that involve cell metabolism reprogramming in cancer cells will becovered. Emphasis will be given to studies that identify key components of the integrated molecular patternincluding receptor tyrosine kinase (RTK) downstream signaling, cell death and mitochondria-related events thatappear to be involved in the resistance of cancer cells to TKI treatments.

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Institute of Health Carlos III (ISCiii)(PI16/00090, PI19/00838 and PI19/01266)

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Spanish Ministry ofEconomy and Competitiveness (BFU2016-80006-P)

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Andalusian Ministry of Equality, Health and SocialPolicies (PI-0198-2016)

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Valencian Ministry of Education, Cultureand Sports (PROMETEO/2019/027)

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FPU predoctoral fellowship (FPU17/00026) from Spanish Ministry ofEducation, Culture and Sport

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The pre-doctoral i-PFIS IIS-enterprise contract in science and technologies inhealth (IFI18/00014) from ISCiii

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Biomedical Research Network Center for Liver and Digestive Diseases(CIBERehd) founded by the ISCiii and co-financed by EuropeanRegional Development Fund (ERDF) "A way to achieve Europe"

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Andalusian Ministry of Economy, Innovation, Science and Employment (BIO-216 and CTS-626)

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