Mechanistic Analysis of a DNA Damage-Induced, PTEN-Dependent Size Checkpoint in Human Cells

Enhancement of cellular senescence in tumours triggers a stable cell growth arrest and activation of an antitumour immune response that can be exploited for cancer therapy. Currently, there are only a limited number of targeted therapies that act by increasing senescence in cancers, but the majority of them are not selective and also target healthy cells. Here we developed a chemogenomic screening to identify compounds that enhance senescence in PTEN-deficient cells without affecting normal cells. By using this approach, we identified casein kinase 2 (CK2) as a pro-senescent target. Mechanistically, we show that Pten loss increases CK2 levels by activating STAT3. CK2 upregulation in Pten null tumours affects the stability of Pml, an essential regulator of senescence. However, CK2 inhibition stabilizes Pml levels enhancing senescence in Pten null tumours. Taken together, our screening strategy has identified a novel STAT3-CK2-PML network that can be targeted for pro-senescence therapy for cancer.

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“…1e). These findings were also validated in a pair of HCT116 isogenic cancer cells with and without PTEN 27 (Fig. 1f).…”

Section: Resultssupporting

confidence: 61%

A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours

et al. 2015

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“…4C) (32). This mutation led to a recovery of AKT and ERK activation levels upon stimulation with fixed K562 cells (Fig.…”

Section: Effect Of Pten Overexpression On Activation Of Akt and Mapkmentioning

confidence: 83%

PTEN Is a Negative Regulator of NK Cell Cytolytic Function

Briercheck

Trotta

Chen

et al. 2015

The Journal of Immunology

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Human NK cells are characterized by their ability to initiate an immediate and direct cytolytic response to virally infected or malignantly transformed cells. Within human peripheral blood, the more mature CD56dim NK cell efficiently kills malignant targets at rest, whereas the less mature CD56bright NK cells cannot. In this study, we show that resting CD56bright NK cells express significantly more phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein when compared with CD56dim NK cells. Consistent with this, forced overexpression of PTEN in NK cells resulted in decreased cytolytic activity, and loss of PTEN in CD56bright NK cells resulted in elevated cytolytic activity. Comparable studies in mice showed PTEN overexpression did not alter NK cell development or NK cell–activating and inhibitory receptor expression yet, as in humans, did decrease expression of downstream NK activation targets MAPK and AKT during early cytolysis of tumor target cells. Confocal microscopy revealed that PTEN overexpression disrupts the NK cell’s ability to organize immunological synapse components including decreases in actin accumulation, polarization of the microtubule organizing center, and the convergence of cytolytic granules. In summary, our data suggest that PTEN normally works to limit the NK cell’s PI3K/AKT and MAPK pathway activation and the consequent mobilization of cytolytic mediators toward the target cell and suggest that PTEN is among the active regulatory components prior to human NK cells transitioning from the noncytolytic CD56bright NK cell to the cytolytic CD56dim NK cells.

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“…Loss of PTEN is very common in GBM with homozygous loss occurring in 70% of cases and loss at the other allele ("second hit") in 40% of cases (Furnari et al, 2007). Loss of function due to truncation mutations, as seen in Patient 2's GBM, have been reported in 22% of GBMs (Brennan et al, 2013;Das et al, 2003;Wang et al, 2008;Kim et al, 2011). Loss of PTEN activates the PI3K/AKT/mTOR pathway.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Genomic Profiling of Recurrent Classic Glioblastoma in a Patient Surviving Eleven Years Following Antineoplaston Therapy

Burzynski¹,

Janicki²,

Burzynski³

2015

CCO

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Most patients with recurrent glioblastoma (RGBM) die within 6 months regardless of treatment. In phase II studies of Antineoplaston A10 and AS2-1 injections (ANP), our investigators have reported objective responses and long-term survival in RGBM. Using a next-generation sequencing (NGS) based assay of 343 cancer-related genes and introns, comprehensive genomic profiling of tumor tissue obtained from a RGBM patient (who remains alive and well) was performed 11 years after diagnosis and permitted assignment of the patient's RGBM to the classical subgroup. The most important genomic alterations included amplification of epidermal growth factor receptor (EGFR), cyclin-dependent kinase inhibitor 2A and 2B (CDKN2A/B), loss of phosphatase and tensin homolog (PTEN) and telomerase reverse transcriptase (TERT) mutation. An analysis of the signaling networks and other targets of ANP therapy was recently performed and presented in this publication. Based on our findings, patients with classical RGBM have a reasonable possibility of responding to ANP therapy and experiencing long-term survival. It is proposed that this subgroup of RGBM patients be enrolled in a genomics-driven clinical trial of ANP therapy.

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Mechanistic Analysis of a DNA Damage-Induced, PTEN-Dependent Size Checkpoint in Human Cells

Cited by 32 publications

References 50 publications

A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours

A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours

PTEN Is a Negative Regulator of NK Cell Cytolytic Function

Comprehensive Genomic Profiling of Recurrent Classic Glioblastoma in a Patient Surviving Eleven Years Following Antineoplaston Therapy

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