PTEN Tumor-Suppressor: The Dam of Stemness in Cancer

Abstract

PTEN is one of the most frequently inactivated tumor suppressor genes in cancer. Loss or variation in PTEN gene/protein levels is commonly observed in a broad spectrum of human cancers, while germline PTEN mutations cause inherited syndromes that lead to increased risk of tumors. PTEN restrains tumorigenesis through different mechanisms ranging from phosphatase-dependent and independent activities, subcellular localization and protein interaction, modulating a broad array of cellular functions including growth, proliferation, survival, DNA repair, and cell motility. The main target of PTEN phosphatase activity is one of the most significant cell growth and pro-survival signaling pathway in cancer: PI3K/AKT/mTOR. Several shreds of evidence shed light on the critical role of PTEN in normal and cancer stem cells (CSCs) homeostasis, with its loss fostering the CSC compartment in both solid and hematologic malignancies. CSCs are responsible for tumor propagation, metastatic spread, resistance to therapy, and relapse. Thus, understanding how alterations of PTEN levels affect CSC hallmarks could be crucial for the development of successful therapeutic approaches. Here, we discuss the most significant findings on PTEN-mediated control of CSC state. We aim to unravel the role of PTEN in the regulation of key mechanisms specific for CSCs, such as self-renewal, quiescence/cell cycle, Epithelial-to-Mesenchymal-Transition (EMT), with a particular focus on PTEN-based therapy resistance mechanisms and their exploitation for novel therapeutic approaches in cancer treatment.

Keywords: PTEN; cancer stem cells; targeted therapy; therapy resistance.

Figure 1

Mechanisms of PTEN-mediated control of cancer stem cells (CSCs) hallmarks. PTEN deficiency promotes self-renewal through inhibitory phosphorylation of FoxO3a [126,136] and GSK3β, which increases nuclear β-catenin localization [127]. Furthermore, it induces STAT3 activation by NFkB-mediated IL6 transcription [129] and CXCR4 expression [135]. MicroRNAs (miR-10b [140], miR-21 [133], miR-106b [139] and TGFβ-induced miR-216a [136]) and PRMT5-mediated methylation [141] are also involved in the downregulation of PTEN and regulation of self-renewal. Hyperactive AKT acts on cell cycle stimulating proliferation trough PAX7 [124], cyclinD1 [142] or C-MYC [143]. PTEN loss may trigger G0 cell cycle arrest and quiescence of CSCs [122,142,144,145,146,147,148,149]. Activation of mTOR is required for CSC survival and can be associated with the activation of collateral pro-survival pathways such as HIF-1α [150]. S100A4 [151] and BMI1 [134], along with several miRNAs (miR-20a/miR-200c [152], miR-17, miR-221/222 [153]) impair PTEN function, thus promoting EMT and metastatic progression. The lncRNA-GAEA inhibits PTEN lipid phosphatase activity, switching on its protein phosphatase activity and promoting the accumulation of EMT master regulators such as TWIST, SNAIL, and YAP [154]. Moreover, activation of the RAS/MAPK pathway [155], NOTCH1 signaling [156], and MAOA [157] cooperate with PTEN/PI3K/AKT axis to promote the EMT program.

Figure 2

Targeting PI3K/PTEN/AKT/mTOR pathways for cancer therapy. Schematic depicting of possible strategies/drugs to overcome PTEN-mediated resistance to conventional therapy in several malignancies. Nervous system cancer: specific PI3K/AKT inhibitors, LY294002 and BKM-120, in combination with conventional chemotherapy, inhibit Glioblastoma Multiforme (GBM) and Sonic Hedgehog Medulloblastoma (SHH-MB) CSCs, respectively. Anti-miR-17 and TAT-Cx43266-283, by mimicking the effects of Connexin 43 (CX43), increase PTEN expression and inhibit glioma stem cells tumorigenic features. Liver cancer: treatment with Celecoxib (cyclooxygenase-2 (COX-2) inhibitor) and rosiglitazone reduce AKT phosphorylation and increase PTEN protein levels, thus affecting cell proliferation. Anti-miR-216a and lupeol, a phytochemical compound, decrease the stem population through PTEN modulation. Prostate cancer: PI3K-mTOR dual inhibitor, NVP-BEZ235, in combination with conventional chemotherapy, leads to significant tumor regression in mice, targeting both prostate cancer progenitors (PCPs) and bulk tumor. I3C (indol-3-carbinol), a derivative of cruciferous vegetables, is able to restore PTEN activity leading to suppression of tumorigenesis. Leukemia: mTOR inhibitor rapamicyn, PI3K-mTOR dual inhibitor, NVP-BEZ235, JQ1 inhibitor targeting c-Myc pathway, and DB1976, a compound that disrupts the interactions between SPI1 and its targets, all result in a significant reduction of leukemic stem cells (L-CSCs). Colon cancer: treatment with rapamicyn, in combination with chemotherapy, inhibits tumor growth. Treatment with anti-miR-106b may overcome radio-resistance in colon cancer. BMP4 (Bone Morphogenetic Protein 4) inhibits PI3K/AKT pathway through PTEN up-regulation. Breast cancer: treatment with PI3K/AKT inhibitors, LY294002 and perifosine, alone or in combination with chemotherapy, reduces mammary stem cell population and tumor growth in mice. Lung cancer: treatment with LY294002, MK2206, and rapamicyn inhibits PI3K/AKT/mTOR pathway acting on the maintenance of lung stem cells through chemokine receptor modulation. Anti-miR-494-3p prevents metastasis and tumor progression while anti-miR-23a is able to upregulate PTEN expression, restoring lung cancer stem cells (LCSCs) sensitivity to chemotherapy.