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Irreversible cell growth arrest, a process termed cellular senescence, is emerging as an intrinsic tumor suppressive mechanism. Oncogene-induced senescence is thought to be invariably preceded by hyperproliferation, aberrant replication, and activation of a DNA damage checkpoint response (DDR), rendering therapeutic enhancement of this process unsuitable for cancer treatment. We previously demonstrated in a mouse model of prostate cancer that inactivation of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (Pten) elicits a senescence response that opposes tumorigenesis. Here, we show that Pten-loss-induced cellular senescence (PICS) represents a senescence response that is distinct from oncogene-induced senescence and can be targeted for cancer therapy. Using mouse embryonic fibroblasts, we determined that PICS occurs rapidly after Pten inactivation, in the absence of cellular proliferation and DDR. Further, we found that PICS is associated with enhanced p53 translation. Consistent with these data, we showed that in mice p53-stabilizing drugs potentiated PICS and its tumor suppressive potential. Importantly, we demonstrated that pharmacological inhibition of PTEN drives senescence and inhibits tumorigenesis in vivo in a human xenograft model of prostate cancer. Taken together, our data identify a type of cellular senescence that can be triggered in nonproliferating cells in the absence of DNA damage, which we believe will be useful for developing a 'pro-senescence' approach for cancer for prevention and therapy., Introduction Cellular senescence describes a terminal arrest of cell growth that is observed in response to various insults including an abnormally high activity of oncogenes (1). After its discovery and [...]

Removal of one kidney stimulates synthesis of RNA and protein, with minimal DNA replication, in all nephron segments of the remaining kidney, resulting in cell growth (increase in cell size) with minimal cell proliferation (increase in cell number). In addition to the compensatory renal hypertrophy caused by nephron loss, pathophysiological renal hypertrophy can occur as a consequence of early uncontrolled diabetes. However, the molecular mechanism underlying renal hypertrophy in these conditions remains unclear. In the present study, we report that deletion of S6 kinase 1 (S6K1) inhibited renal hypertrophy seen following either contralateral nephrectomy or induction of diabetes. In wild-type mice, hypertrophic stimuli increased phosphorylation of 40S ribosomal protein S6 (rpS6), a known target of S6K1. Immunoblotting analysis revealed that [S6K1.sup.-/-] mice exhibited moderately elevated basal levels of rpS6, which did not increase further in response to the hypertrophic stimuli. Northern blotting indicated a moderate upregulation of S6K2 expression in the kidneys of [S6K1.sup.-/-] mice. Phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1, another downstream target of the mammalian target of rapamycin (roTOR), was stimulated to equivalent levels in [S6K1.sup.-/-] and [S6K1.sup.+/+] littermates during renal hypertrophy, indicating that mTOR was still activated in the [S6K1.sup.-/-] mice. The highly selective roTOR inhibitor, rapamycin, inhibited increased phosphorylation of rpS6 and blocked 60-70% of the hypertrophy seen in wild-type mice but failed to prevent the ~10% hypertrophy seen in [S6K1.sup.-/-] mice in response to uninephrectomy (UNX) although it did inhibit the basal rpS6 phosphorylation. Thus the present study provides the first genetic evidence that S6K1 plays a major role in the development of compensatory renal hypertrophy as well as diabetic renal hypertrophy and indicates that UNX- and diabetes-mediated roTOR activation can selectively activate S6K1 without activating S6K2. compensatory renal hypertrophy; streptozotocin; mammalian target of rapamycin complex 1 signaling; S6 kinases; rapamycin

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 [...]

Author(s): Abul Arif [1]; Fulvia Terenzi [1]; Alka A. Potdar [2]; Jie Jia [1]; Jessica Sacks [1]; Arnab China [1]; Dalia Halawani [1]; Kommireddy Vasu [1]; Xiaoxia Li [3]; J. [...]

Author(s): Sung Hee Um [1]; Francesca Frigerio [1]; Mitsuhiro Watanabe [2]; Frédéric Picard [2, 4]; Manel Joaquin [1]; Melanie Sticker [1]; Stefano Fumagalli [1]; Peter R. Allegrini [3]; Sara C. [...]

Author(s): Mario Pende [1]; Sara C. Kozma [1]; Muriel Jaquet [2]; Viola Oorschot [3]; Rémy Burcelin [2]; Yannick Le Marchand-Brustel [4]; Judith Klumperman [3]; Bernard Thorens [2]; George Thomas (corresponding [...]

A study of the activation of p70 and p85 S6 kinase by a pathway not influenced by p21ras reveals that the activation is stimulated by the sequential activation of the GDP-GTP exchange factor Sos. The p70 and p85 enzymes are two different forms of the same kinase and are essential for mitogenesis. The cells transformed by the activation of this enzyme exhibit increased phosphorylation, which is different from the activities caused by p42 and p44 kinases.