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Cancer cells exhibit an aberrant metabolism that facilitates more efficient production of biomass and hence tumor growth and progression. However, the genetic cues modulating this metabolic switch remain largely undetermined. We identified a metabolic function for the promyelocytic leukemia (PML) gene, uncovering an unexpected role for this bona fide tumor suppressor in breast cancer cell survival. We found that PML acted as both a negative regulator of PPARγ coactivator 1A (PGC1A) acetylation and a potent activator of PPAR signaling and fatty acid oxidation. We further showed that PML promoted ATP production and inhibited anoikis. Importantly, PML expression allowed luminal filling in 3D basement membrane breast culture models, an effect that was reverted by the pharmacological inhibition of fatty acid oxidation. Additionally, immunohistochemical analysis of breast cancer biopsies revealed that PML was overexpressed in a subset of breast cancers and enriched in triple-negative cases. Indeed, PML expression in breast cancer correlated strikingly with reduced time to recurrence, a gene signature of poor prognosis, and activated PPAR signaling. These findings have important therapeutic implications, as PML and its key role in fatty acid oxidation metabolism are amenable to pharmacological suppression, a potential future mode of cancer prevention and treatment., Introduction It is well established that reprogramming of cellular metabolism by cancer genes is a key step in cancer pathogenesis and progression (1). Indeed, more than a century ago, Otto [...]

Cellular senescence has been recently shown to have an important role in opposing tumour initiation and promotion. Senescence induced by oncogenes or by loss of tumour suppressor genes is thought to critically depend on induction of the [p19.sup.Arf]-p53 pathway. The Skp2 E3-ubiquitin ligase can act as a proto-oncogene and its aberrant overexpression is frequently observed in human cancers. Here we show that although Skp2 inactivation on its own does not induce cellular senescence, aberrant proto-oncogenic signals as well as inactivation of tumour suppressor genes do trigger a potent, tumour- suppressive senescence response in mice and cells devoid of Skp2. Notably, Skp2 inactivation and oncogenic-stress-driven senescence neither elicit activation of the [p19.sup.Arf]-p53 pathway nor DNA damage, but instead depend on Atf4, p27 and p21. We further demonstrate that genetic Skp2 inactivation evokes cellular senescence even in oncogenic conditions in which the [p19.sup.Arf]-p53 response is impaired, whereas a Skp2-SCF complex inhibitor can trigger cellular senescence in p53/Pten-deficient cells and tumour regression in preclinical studies. Our findings therefore provide proof-of-principle evidence that pharmacological inhibition of Skp2 may represent a general approach for cancer prevention and therapy., Cellular senescence represents an irreversible form of cell-cycle arrest that can be triggered by a variety of insults. Induction of cellular senescence (for example, by oncogenic Ras) results in [p19.sup.Arf] [...]

Autophagy can promote cell survival or cell death, but the molecular basis underlying its dual role in cancer remains obscure. Here we demonstrate that [[Delta].sup.9]-tetrahydrocannabinol (THC), the main active component of marijuana, induces human glioma cell death through stimulation of autophagy. Our data indicate that THC induced ceramide accumulation and eukaryotic translation initiation factor 2[alpha] (eIF2[alpha]) phosphorylation and thereby activated an ER stress response that promoted autophagy via tribbles homolog 3-dependent (TRB3-dependent) inhibition of the Akt/mammalian target of rapamycin complex 1 (mTORC1) axis. We also showed that autophagy is upstream of apoptosis in cannabinoid-induced human and mouse cancer cell death and that activation of this pathway was necessary for the antitumor action of cannabinoids in vivo. These findings describe a mechanism by which THC can promote the autophagic death of human and mouse cancer cells and provide evidence that cannabinoid administration may be an effective therapeutic strategy for targeting human cancers., Introduction Macro-autophagy, hereafter referred to as "autophagy," is a highly conserved cellular process in which cytoplasmic materials--including organelles--are sequestered into double-membrane vesicles called autophagosomes and delivered to lysosomes for degradation [...]

Nuclear exclusion of the PTEN (phosphatase and tensin homologue deleted in chromosome 10) tumour suppressor has been associated with cancer progression (1-6). However, the mechanisms leading to this aberrant PTEN [...]

Numerous studies have established a causal link between aberrant mammalian target of rapamycin (mTOR) activation and tumorigenesis, indicating that mTOR inhibition may have therapeutic potential. In this study, we show that rapamycin and its analogs activate the MAPK pathway in human cancer, in what represents a novel mTORC1-MAPK feedback loop. We found that tumor samples from patients with biopsy-accessible solid tumors of advanced disease treated with RAD001, a rapamycin derivative, showed an administration schedule--dependent increase in activation of the MAPK pathway. RAD001 treatment also led to MAPK activation in a mouse model of prostate cancer. We further show that rapamycin-induced MAPK activation occurs in both normal cells and cancer cells lines and that this feedback loop depends on an S6K-PI3K-Ras pathway. Significantly, pharmacological inhibition of the MAPK pathway enhanced the antitumoral effect of mTORC1 inhibition by rapamycin in cancer cells in vitro and in a xenograft mouse model. Taken together, our findings identify MAPK activation as a consequence of mTORC1 inhibition and underscore the potential of a combined therapeutic approach with mTORC1 and MAPK inhibitors, currently employed as single agents in the clinic, for the treatment of human cancers., Introduction Mammalian target of rapamycin (mTOR) integrates various cues, including growth factors, nutrients, energy, and stress, to regulate protein synthesis, cell growth and proliferation, early development, and memory, under physiological [...]

Nuclear exclusion of the PTEN (phosphatase and tensin homologue deleted in chromosome 10) tumour suppressor has been associated with cancer progression. However, the mechanisms leading to this aberrant PTEN localization in human cancers are currently unknown. We have previously reported that ubiquitinylation of PTEN at specific lysine residues regulates its nuclear–cytoplasmic partitioning. Here we show that functional promyelocytic leukaemia protein (PML) nuclear bodies co-ordinate PTEN localization by opposing the action of a previously unknown PTEN-deubiquitinylating enzyme, herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7), and that the integrity of this molecular framework is required for PTEN to be able to enter the nucleus. We find that PTEN is aberrantly localized in acute promyelocytic leukaemia, in which PML function is disrupted by the PML–RARα fusion oncoprotein. Remarkably, treatment with drugs that trigger PML–RARα degradation, such as all-trans retinoic acid or arsenic trioxide, restore nuclear PTEN. We demonstrate that PML opposes the activity of HAUSP towards PTEN through a mechanism involving the adaptor protein DAXX (death domain-associated protein). In support of this paradigm, we show that HAUSP is overexpressed in human prostate cancer and is associated with PTEN nuclear exclusion. Thus, our results delineate a previously unknown PML–DAXX–HAUSP molecular network controlling PTEN deubiquitinylation and trafficking, which is perturbed by oncogenic cues in human cancer, in turn defining a new deubiquitinylation-dependent model for PTEN subcellular compartmentalization. [ABSTRACT FROM AUTHOR]

Lrf has been previously described as a powerful proto-oncogene. Here we surprisingly demonstrate that Lrf plays a critical oncosuppressive role in the prostate. Prostate specific inactivation of Lrf leads to a dramatic acceleration of Pten-loss-driven prostate tumorigenesis through a bypass of Pten-loss-induced senescence (PICS). We show that LRF physically interacts with and functionally antagonizes SOX9 transcriptional activity on key target genes such as MIA, which is involved in tumor cell invasion, and H19, a long non-coding RNA precursor for an Rb-targeting miRNA. Inactivation of Lrf in vivo leads to Rb down-regulation, PICS bypass and invasive prostate cancer. Importantly, we found that LRF is genetically lost, as well as down-regulated at both the mRNA and protein levels in a subset of human advanced prostate cancers. Thus, we identify LRF as a context-dependent cancer gene that can act as an oncogene in some contexts but also displays oncosuppressive-like activity in Pten−/− tumors.

The article presents research which examined non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation. The authors of the research found that CB2 receptors are capable of controlling neural progenitor cell proliferation and neurosphere generation in vitro.

A correction to the article "Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence" that was published in the 2010 issue is presented.

Autophagy can promote cell survival or cell death, but the molecular basis underlying its dual role in cancer remains obscure. Here we demonstrate that Δ9-tetrahydrocannabinol (THC), the main active component of marijuana, induces human glioma cell death through stimulation of autophagy. Our data indicate that THC induced ceramide accumulation and eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and thereby activated an ER stress response that promoted autophagy via tribbles homolog 3-dependent (TRB3-dependent) inhibition of the Akt/mammalian target of rapamycin complex 1 (mTORC1) axis. We also showed that autophagy is upstream of apoptosis in cannabinoid-induced human and mouse cancer cell death and that activation of this pathway was necessary for the antitumor action of cannabinoids in vivo. These findings describe a mechanism by which THC can promote the autophagic death of human and mouse cancer cells and provide evidence that cannabinoid administration may be an effective therapeutic strategy for targeting human cancers. [ABSTRACT FROM AUTHOR]

One reported function of the tumor suppressor p19(Arf) is to stabilize p53, providing a critical checkpoint in the response to oncogenic insults. Acute loss of Pten leads to an increase in the abundance of p19(Arf), p53, and p21 proteins as part of a fail-safe senescence response. Here, we report that loss of p19(Arf) in prostate epithelium does not accelerate-but rather partially inhibits-the prostate cancer phenotype of Pten-deficient mice. Moreover, cellular senescence and a further decrease in the number of pre-neoplastic glands were observed in prostates of the Pten-p19(Arf) double-mutant mice. In both prostate epithelium and primary mouse embryo fibroblasts (MEFs), the increase in p53 protein abundance found upon loss of Pten was unaffected by the simultaneous loss of p19(Arf). However, in contrast to that in the prostate epithelium, p19(Arf) deficiency in MEFs lacking Pten abolished cell senescence and promoted hyperproliferation and transformation despite the unabated increase in p53 abundance. Consistent with the effect of p19(Arf) loss in Pten-deficient mouse prostate, we found that in human prostate cancers, loss of PTEN was not associated with loss of p14(ARF) (the human equivalent of mouse p19(Arf)). Collectively, these data reveal differential consequences of p19(Arf) inactivation in prostate cancer and MEFs upon Pten loss that are independent of the p53 pathway.

Cannabinoids, the active components of marijuana and their endogenous counterparts, act on the brain and many other organs through the widely expressed CB1 cannabinoid receptor. In contrast, the CB2 cannabinoid receptor is abundant in the immune system and shows a restricted expression pattern in brain cells. CB2-selective agonists are, therefore, very attractive therapeutic agents as they do not cause CB1-mediated psychoactive effects. CB2 receptor expression in brain has been partially examined in differentiated cells, while its presence and function in neural progenitor cells remain unknown. Here we show that the CB2 receptor is expressed, both in vitro and in vivo, in neural progenitors from late embryonic stages to adult brain. Selective pharmacological activation of the CB2 receptor in vitro promotes neural progenitor cell proliferation and neurosphere generation, an action that is impaired in CB2-deficient cells. Accordingly, in vivo experiments evidence that hippocampal progenitor proliferation is increased by administration of the CB2-selective agonist HU-308. Moreover, impaired progenitor proliferation was observed in CB2-deficient mice both in normal conditions and on kainate-induced excitotoxicity. These findings provide a novel physiological role for the CB2 cannabinoid receptor and open a novel therapeutic avenue for manipulating neural progenitor cell fate.