Molecular mechanisms involved in DNA repair in human cancers: An overview of PI3k/Akt signaling and PIKKs crosstalk

Abstract

The cellular genome is frequently subjected to abundant endogenous and exogenous factors that induce DNA damage. Most of the Phosphatidylinositol 3-kinase-related kinases (PIKKs) family members are activated in response to DNA damage and are the most important DNA damage response (DDR) proteins. The DDR system protects the cells against the wrecking effects of these genotoxicants and repairs the DNA damage caused by them. If the DNA damage is severe, such as when DNA is the goal of chemo-radiotherapy, the DDR drives cells toward cell cycle arrest and apoptosis. Some intracellular pathways, such as PI3K/Akt, which is overactivated in most cancers, could stimulate the DDR process and failure of chemo-radiotherapy with the increasing repair of damaged DNA. This signaling pathway induces DNA repair through the regulation of proteins that are involved in DDR like BRCA1, HMGB1, and P53. In this review, we will focus on the crosstalk of the PI3K/Akt and PIKKs involved in DDR and then discuss current achievements in the sensitization of cancer cells to chemo-radiotherapy by PI3K/Akt inhibitors.

From inflammatory bowel disease to colorectal cancer: what’s the role of miRNAs?

“…Chronic inflammation in long term leads to epithelial cells moving toward Dysplasia and ultimately adenocarcinoma. In this long course, several factors such as DNA damage [ 20 ] and mutation in TP53 tumor suppressant gene, immune cells, and cytokines produced by them, signaling pathways such as NFκB, STAT3, AKT/PI3K [ 21 ], and WNT/β-Catenin [ 22 ] are involved and miRNAs are also associated with all of these factors in some way. It seems that targeting some of them can be useful in stopping this dangerous course or more effective treatment of colorectal cancer.…”

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“…ATM, ATR, and DNA-PKcs, such as PI3K-like kinase (PIKK) family members, are activated in response to DNA damage and induce γH2AX production [12]. Then, activated PIKK family member proteins initiate the PI3K/AKT/mTOR signaling pathway to repair DNA damage, leading to cell cycle arrest [13,14]. Furthermore, excessive intracellular oxygen free radicals can damage the mitochondria and initiate mitochondrial oxidative stress [15].…”