PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers

Abstract

Multidrug resistance (MDR) is the dominant challenge in the failure of chemotherapy in cancers. Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that spreads intracellular signal cascades and regulates a variety of cellular processes. PI3Ks are considered significant causes of chemoresistance in cancer therapy. Protein kinase B (AKT) is also a significant downstream effecter of PI3K signaling, and it modulates several pathways, including inhibition of apoptosis, stimulation of cell growth, and modulation of cellular metabolism. This review highlights the aberrant activation of PI3K/AKT as a key link that modulates MDR. We summarize the regulation of numerous major targets correlated with the PI3K/AKT pathway, which is further related to MDR, including the expression of apoptosis-related protein, ABC transport and glycogen synthase kinase-3 beta (GSK-3β), synergism with nuclear factor kappa beta (NF-κB) and mammalian target of rapamycin (mTOR), and the regulation of glycolysis.

Fig. 1. As a major downstream effector of receptor tyrosine kinase (RTK) and G protein-coupled receptors, PI3K activates various downstream effectors by generating phospholipids, transducing signals of various growth factors and cytokines into intracellular information.

The main lipid substrate of PTEN is PIP 3 and indeed PTEN acts as a negative regulator of PI3K/AKT signaling. Among the upstream signaling networks, Akt inactivate TSC1/2 and activate mTORC1. mTORC2 directly phosphorylates Akt at S473 residue leading to its complete activation. This activation of the PI3K/Akt pathway is opposed by PTEN.

Fig. 2. The PI3K/AKT pathway regulates the gene expression of ABC transporters by activating downstream targets, such as NF-κB and Nfr2, resulting in over-expression of P-gp, MRP1, BCRP.

Thus, accelerating the transport of anticancer drugs by ABC transporter to the outside that leading to MDR.

Fig. 3. A dysfunctional PI3K/AKT pathway serves as a hub to regulate many cellular processes that are involved in MDR including apoptosis, ABC transporter activity, mTOR pathway, and tumor metabolism.

Note: The PI3K/AKT pathway enhances drug efflux through effective expression of ABC transporter. Aerobic glycolysis is the key energy supplier to the metabolic adaptation of cancer cells for MDR. The PI3K/AKT pathway affects tumor proliferation by regulating mTOR, GSK-3β, and NF-κB. The PI3K/AKT pathway triggers XIAP to suppress the activity of caspase-3 inhibiting apoptosis. The decrease of caspase-8 will reduce migration of Bid to mitochondria, and slim down the activation of Bax and Bim, which lead to the decrease of mitochondrial membrane permeability (MOMP) and the release of cytochrome c. Caspase-8 also regulates the expression of caspase-3 to achieve cell apoptosis. The P13K/AKT/mTOR may also underlie MDR in tumor cells through inducing dysregulation of miRNA.