Abstract
Cancer resistance to chemotherapy, radiotherapy and molecular-targeted agents is a major obstacle to successful cancer therapy. Herein, aberrant activation of the phosphatidyl-inositol-3-kinase (PI3K)/protein kinase B (Akt) pathway is one of the most frequently deregulated pathways in cancer cells and has been associated with multiple aspects of therapy resistance. These include, for example, survival under stress conditions, apoptosis resistance, activation of the cellular response to DNA damage and repair of radiation-induced or chemotherapy-induced DNA damage, particularly DNA double strand breaks (DSB). One further important, yet not much investigated aspect of Akt-dependent signaling is the regulation of cell metabolism. In fact, many Akt target proteins are part of or involved in the regulation of metabolic pathways. Furthermore, recent studies revealed the importance of certain metabolites for protection against therapy-induced cell stress and the repair of therapy-induced DNA damage. Thus far, the likely interaction between deregulated activation of Akt, altered cancer metabolism and therapy resistance is not yet well understood. The present review describes the documented interactions between Akt, its target proteins and cancer cell metabolism, focusing on antioxidant defense and DSB repair. Furthermore, the review highlights potential connections between deregulated Akt, cancer cell metabolism and therapy resistance of cancer cells through altered DSB repair and discusses potential resulting therapeutic implications.
Highlights
Radiotherapy, in addition to surgery and chemotherapy, is one of the three main standard therapies for cancer treatment
The presence of reactive oxygen species (ROS) leads to the activation of transcription of genes involved in the antioxidant defense; these are mainly regulated by the stress sensors AMPK and Akt via the transcription factor Nrf2 and in part via Forkhead-Box-Protein O3 (FoxO) and HIF1, respectively [18,108]
As this review focuses on metabolic requirements for double strand breaks (DSB) repair, we will briefly introduce the main metabolites required for the modification of DNA and proteins during the DNA damage response (DDR)
Summary
Radiotherapy, in addition to surgery and chemotherapy, is one of the three main standard therapies for cancer treatment. Aberrant activation of this pathway supports cancer development and progression as well as resistance to standard or molecularly targeted cancer therapies through a variety of cellular activities These include for example protein synthesis, cell cycle progression, proliferation, survival, angiogenesis, metastasis and cancer metabolism [46,50]. The survival kinase Akt exerts multifaceted roles in regulating the DDR, DSB repair and cell survival, under stress conditions, thereby contributing to therapy resistance (for a review see [50,51,52]). We will highlight a new facet of Akt-dependent therapy resistance by regulation of metabolic pathways with relevance to the DDR, DSB repair and radiation resistance
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
