PTEN/PTENP1: ‘Regulating the regulator of RTK-dependent PI3K/Akt signalling’, new targets for cancer therapy

Abstract

Regulation of the PI-3 kinase (PI3K)/Akt signalling pathway is essential for maintaining the integrity of fundamental cellular processes, cell growth, survival, death and metabolism, and dysregulation of this pathway is implicated in the development and progression of cancers. Receptor tyrosine kinases (RTKs) are major upstream regulators of PI3K/Akt signalling. The phosphatase and tensin homologue (PTEN), a well characterised tumour suppressor, is a prime antagonist of PI3K and therefore a negative regulator of this pathway. Loss or inactivation of PTEN, which occurs in many tumour types, leads to overactivation of RTK/PI3K/Akt signalling driving tumourigenesis. Cellular PTEN levels are tightly regulated by a number of transcriptional, post-transcriptional and post-translational regulatory mechanisms. Of particular interest, transcription of the PTEN pseudogene, PTENP1, produces sense and antisense transcripts that exhibit post-transcriptional and transcriptional modulation of PTEN expression respectively. These additional levels of regulatory complexity governing PTEN expression add to the overall intricacies of the regulation of RTK/PI-3 K/Akt signalling. This review will discuss the regulation of oncogenic PI3K signalling by PTEN (the regulator) with a focus on the modulatory effects of the sense and antisense transcripts of PTENP1 on PTEN expression, and will further explore the potential for new therapeutic opportunities in cancer treatment.

Cryptotanshinone Inhibites Bladder Cancer Cell Proliferation and Promotes Apoptosis via the PTEN/PI3K/AKT Pathway

“…In this study, we found that a new Akt inhibitory agent, CTT, induced significant decreases in cell proliferation and suppressed the migration and invasion of bladder cells. In addition, we found that the expression level of PTEN increased after CTT treatment, which indicated that PTEN was a key modulator of the induction of PI3K/Akt signalling [24]. Inhibition of PTEN expression reversed the inhibitory effects of CTT.…”

Long non‑coding RNA GAS5 increases the radiosensitivity of A549 cells through interaction with the miR‑21/PTEN/Akt axis

“…There are several potential binding sites of miR-21 on the PTEN 3'UTR, such as GAUAAG and UCUG*UG*GCUA (43,44). PTEN is an inhibitor of the PI3K/Akt signaling pathway (45), and the PTEN/Akt axis is a pivotal regulatory pathway in IR-induced cell apoptosis. He et al demonstrated that overexpression of circVRK1 could reverse the radioresistance of esophageal squamous carcinoma cells by regulating the miR-624-3p/PTEN/PI3K/Akt signaling pathway (40).…”

Targeting PI3K in cancer: mechanisms and advances in clinical trials

“…In PTEN knock-in mice harboring two cancer-associated PTEN mutations, PTENC124S and PTENG129E inhibit the PTEN lipid-phosphatase activity in a dominant negative manner, leading to increased activity of PI3K signaling and tumorigenesis [20]. Moreover, in PTEN-deficient cancer, the main carcinogenic driving force is the overactivation of AKT caused by the loss of PTEN lipid phosphatase function [20,25].…”

“…NVP BEZ235 (dactolisib) is a dual PI3K/mTOR inhibitor and is currently in Phase I/II clinical trials. It is an imidazo [4,5-c] quinoline derivative compound that binds to the ATP-binding cleft of PI3K and mTOR kinase, inhibiting their catalytic activities [25]. BEZ235 exhibited satisfactory anticancer effects in preclinical studies in several types of cancer, including the following: triple-negative breast cancer, lung cancer, melanoma, colorectal cancer, renal cancer, prostate cancer, lymphoma, and mucinous adenocarcinoma of the ovary [73][74][75][76][77][78][79][80][81][82][83][84][85].…”