PTEN in the maintenance of genome integrity: From DNA replication to chromosome segregation.

Faithful DNA replication and accurate chromosome segregation are the key machineries of genetic transmission. Disruption of these processes represents a hallmark of cancer and often results from loss of tumor suppressors. PTEN is an important tumor suppressor that is frequently mutated or deleted in human cancer. Loss of PTEN has been associated with aneuploidy and poor prognosis in cancer patients. In mice, Pten deletion or mutation drives genomic instability and tumor development. PTEN deficiency induces DNA replication stress, confers stress tolerance, and disrupts mitotic spindle architecture, leading to accumulation of structural and numerical chromosome instability. Therefore, PTEN guards the genome by controlling multiple processes of chromosome inheritance. Here, we summarize current understanding of the PTEN function in promoting high-fidelity transmission of genetic information. We also discuss the PTEN pathways of genome maintenance and highlight potential targets for cancer treatment.

Cell Cycle Control by PTEN.

Continuous and error-free chromosome inheritance through the cell cycle is essential for genomic stability and tumor suppression. However, accumulation of aberrant genetic materials often causes the cell cycle to go awry, leading to malignant transformation. In response to genotoxic stress, cells employ diverse adaptive mechanisms to halt or exit the cell cycle temporarily or permanently. The intrinsic machinery of cycling, resting, and exiting shapes the cellular response to extrinsic stimuli, whereas prevalent disruption of the cell cycle machinery in tumor cells often confers resistance to anticancer therapy. Phosphatase and tensin homolog (PTEN) is a tumor suppressor and a guardian of the genome that is frequently mutated or deleted in human cancer. Moreover, it is increasingly evident that PTEN deficiency disrupts the fundamental processes of genetic transmission. Cells lacking PTEN exhibit cell cycle deregulation and cell fate reprogramming. Here, we review the role of PTEN in regulating the key processes in and out of cell cycle to optimize genomic integrity.

PTEN at the interface of immune tolerance and tumor suppression.

BACKGROUND: PTEN is well known to function as a tumor suppressor that antagonizes oncogenic signaling and maintains genomic stability. The PTEN gene is frequently deleted or mutated in human cancers and the wide cancer spectrum associated with PTEN deficiency has been recapitulated in a variety of mouse models of Pten deletion or mutation. Pten mutations are highly penetrant in causing various types of spontaneous tumors that often exhibit resistance to anticancer therapies including immunotherapy. Recent studies demonstrate that PTEN also regulates immune functionality. OBJECTIVE: To understand the multifaceted functions of PTEN as both a tumor suppressor and an immune regulator. METHODS: This review will summarize the emerging knowledge of PTEN function in cancer immunoediting. In addition, the mechanisms underlying functional integration of various PTEN pathways in regulating cancer evolution and tumor immunity will be highlighted. RESULTS: Recent preclinical and clinical studies revealed the essential role of PTEN in maintaining immune homeostasis, which significantly expands the repertoire of PTEN functions. Mechanistically, aberrant PTEN signaling alters the interplay between the immune system and tumors, leading to immunosuppression and tumor escape. CONCLUSION: Rational design of personalized anti-cancer treatment requires mechanistic understanding of diverse PTEN signaling pathways in modulation of the crosstalk between tumor and immune cells.

PTEN regulates PLK1 and controls chromosomal stability during cell division.

PTEN functions as a guardian of the genome through multiple mechanisms. We have previously established that PTEN maintains the structural integrity of chromosomes. In this report, we demonstrate a fundamental role of PTEN in controlling chromosome inheritance to prevent gross genomic alterations. Disruption of PTEN or depletion of PTEN protein phosphatase activity causes abnormal chromosome content, manifested by enlarged or polyploid nuclei. We further identify polo-like kinase 1 (PLK1) as a substrate of PTEN phosphatase. PTEN can physically associate with PLK1 and reduce PLK1 phosphorylation in a phosphatase-dependent manner. We show that PTEN deficiency leads to PLK1 phosphorylation and that a phospho-mimicking PLK1 mutant causes polyploidy, imitating functional deficiency of PTEN phosphatase. Inhibition of PLK1 activity or overexpression of a non-phosphorylatable PLK1 mutant reduces the polyploid cell population. These data reveal a new mechanism by which PTEN controls genomic stability during cell division.

NOK mediated mitogenic signaling is altered by P203L and V395I mutations.

The novel oncogene with kinase-domain (NOK), is an atypical receptor protein tyrosine kinase with potent oncogenic potential. In the current study, we generated two point mutations (P203L and V395I) on NOK gene. NOK(P203L) is identical to serine/threonine/tyrosine kinase 1 (STYK1), the aliases of NOK, while the V395I mutation was recovered from human glioblastoma. Both mutations did not impair NOK kinase activities, but V395I inhibited NOK autophosphorylation. Although with overall inhibition, both STYK1 and V395I affected the activities of extracellular regulated protein kinase (ERK), Akt and signal transducer and activator of transcription (STAT) differently in HEK293T cells versus HeLa and BaF3 stable cells The proliferation potentials for both STYK1 and V395I were significantly inhibited. Single mutation at either site was sufficient to abolish the IL-3 independent growth and the anchor-independent growth of of BaF3 stable cells. Overall, our data indicates that both P203 and V395 residues on NOK are important for NOK mediated mitogenic signaling, and the substitutions of P203L and V395I may selectively affect certain mitogenic signaling cascades in a tissue specific manner.

MicroRNA miR-491-5p targeting both TP53 and Bcl-XL induces cell apoptosis in SW1990 pancreatic cancer cells through mitochondria mediated pathway.

MicroRNA (miRNA) actively participates in a broad range of cellular processes such as proliferation, differentiation, cell survival and apoptosis. Deregulated expression of miRNA may affect cell growth and eventually lead to cancer. In this study, we found that hsa-miR491-5p (miR491-5p) displays a significantly high level of expression in normal human pancreas tissue versus pancreatic cancer cells. Targeted site prediction indicated that both Bcl-XL and TP53 contain miR-491-5p recognizing sites in their 3' UTRs. Overexpression of miR-491-5p in the pancreatic cancer cell line SW1990 effectively inhibited both endogenous Bcl-XL and TP53 gene expressions. Mutagenesis at the seed match region of both targeted genes further confirmed the specificity of miR491-5p recognition. Cell proliferation rate was inversely related to the increased doses of miR-491-5p. Flow cytometric analysis showed that the proportions of total apoptotic and early apoptotic cells were significantly induced as the dose of miR491-5p increased. Moreover, a mechanistic study indicated that miR-R491-5p-mediated cell apoptosis was associated with the activation of intrinsic mitochondria mediated pathways. miR491-5p also markedly inhibited mitogenic signaling pathways such as STAT3 and PI-3K/Akt, but not Ras/MAPK. Thus, our results demonstrated that miR491-5p could effectively target both Bcl-xL and TP53 and induce cell apoptosis independent of TP53.