A New Twist in Protein Kinase B/Akt Signaling: Role of Altered Cancer Cell Metabolism in Akt-Mediated Therapy Resistance

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.

Metabolism of cancer cells commonly responds to irradiation by a transient early mitochondrial shutdown

“…DNA repair demands high energy inputs, which potentially links cancer cell metabolism and resistance to irradiation ( Götting et al., 2020 ; Rashmi et al., 2018 ; Tang et al., 2018 ; Turgeon et al., 2018 ). The genetic and metabolic capacity of cells to repair radiation-induced lethal DNA lesions with high efficiency is considered as one critical determinant of radiation resistance ( Mladenov et al., 2013 ; Roos et al., 2015 ).…”

The ester derivatives obtained by C‐ring modification of podophyllotoxin‐induced apoptosis and inhibited proliferation in Hemangioma Endothelial Cells via downregulation of PI3K/Akt signaling pathway

“…The PI3K/Akt signaling pathway plays an important role in regulating various cell functions, including metabolism, growth, proliferation, survival, transcription, and protein synthesis (Li et al, 2019). Aberrant activation of the PI3K/Akt pathway is one of the most frequently deregulated pathways in cancer cells (Gotting et al, 2020). Research by Yan Mei et al identified distinct patterns of oncogenic pathways activation at different stages of breast cancer and uncovered five oncogenic pathways that were activated in both human and mouse breast cancers, including PI3K/Akt signaling pathway (Mei et al, 2018).…”

Rapamycin Plus Doxycycline Combination Affects Growth Arrest and Selective Autophagy-Dependent Cell Death in Breast Cancer Cells

“…There are increasing data about metabolic rewiring and alterations in cellular metabolism after different chemotherapeutic treatments. It has been observed that the administered treatments could modulate cellular mechanisms, including alterations in the activation of autophagy, oxidative phosphorylation (OXPHOS) or Warburg reverse Warburg effects cell type and treatment dependently [ 40 , 41 ]. For instance, doxorubicin causes DNA damage and related apoptosis; simultaneously, it has metabolism-interfering effects.…”