Gastric cancer (GC) imposes a significant health burden around the globe despite its declining incidence. GC is often diagnosed in advanced stages and carries a poor prognosis. In depth understanding of molecular underpinnings of GC has lagged behind many other cancers of its magnitude, as a result our knowledge base for identifying germline susceptibility traits for risk and somatic drivers of progression (to identify novel therapeutic targets) is limited. A few germline (PLCE1) and somatic (ERBB2, ERBB3, PTEN, PI3K/AKT/mTOR, FGF, TP53, CDH1, and c-MET) alterations are emerging and some are being pursued in the clinic. Novel somatic gene targets, Arid1a, FAT4, and MLL/MLL3 are of interest. Clinically, variations in the therapeutic approaches for localized GC are evident by geographic regions. These are driven by preferences for the adjunctive strategies and the extent of surgery coupled with philosophical divides. However, there is a greater uniformity in approaches to metastatic cancer, an incurable condition. Having realized only modest successes, the momentum is building for carrying out more phase 3 comparative trials and some are using biomarker-based patient selection. Overall, rapid progress in biotechnology is improving our molecular understanding and can help with new drug discovery. The future prospects are excellent for defining biomarker-based subsets of patients and application of specific therapeutics. However, many challenges remain to be tackled. Here we review representative molecular and clinical dimensions of GC.

The persistent activation of signaling cascades results in dramatic consequences that include loss of cellular growth control and neoplastic transformation. We show here that phosphoinositide 3-kinase (PI 3-kinase) and its mediator Akt were constitutively activated in pancreatic cancer and that this might be due to the aberrant expression of their natural antagonist MMAC/PTEN. Indeed, our results show that MMAC/PTEN expression was either lost or significantly reduced in five of eight cell lines and in twelve of seventeen tumor specimens examined. That the poor expression of MMAC/PTEN in pancreatic cancer cells could be due to promoter methylation was indicated by methylation-specific PCR analysis. Our studies also indicated that PI 3-kinase targeted two important transcription factors in pancreatic cancer cells. The ability of constitutively activated NF-jB to induce gene expression and the stabilization of c-MYC protein by decreased phosphorylation of Thr58 were both dependent on PI 3-kinase activity. When pancreatic cancer cells were treated with a peptide antagonist of NF-jB nuclear translocation, or stably transfected with a dominant-negative mutant of MYC, their proliferation was markedly inhibited. Taken together, these data indicate that the aberrant expression of MMAC/PTEN contributes to the activation of the PI 3-kinase/Akt pathway and its transcription factor mediators in pancreatic cancer.

The phosphoinositide 3-kinase (PI 3-kinase) pathway has been implicated in the activation of the proinflammatory transcription factor nuclear factor B (NFB). To investigate the role of this pathway in NFB activation, we employed mutated in multiple advanced cancers/phosphatase and tensin homologue (MMAC/PTEN), a natural antagonist of PI 3-kinase activity. Our results show that cytokine-induced DNA binding and transcriptional activities of NFB were both inhibited in a glioma cell line that was stably transfected with MMAC/PTEN. The ability of interleukin-1 (IL-1) to induce inhibitor (IB) degradation or nuclear translocation of NFB was, however, unaffected by MMAC/PTEN expression, suggesting that PI 3-kinase utilizes another equally important mechanism to control NFB activation. It is conceivable that NFB is directly phosphorylated through such a mechanism because treatment with protein phosphatase 2A significantly reduced its DNA binding activity. Moreover, IL-1-induced phosphorylation of p50 NFB was potently inhibited in MMAC/PTEN-expressing cells. Whereas the mediators of NFB phosphorylation remain to be identified, IL-1 was found to induce physical interactions between the PI 3-kinase target Akt kinase and the IB⅐IB kinase complex. Physical interactions between these proteins were antagonized by MMAC/PTEN consistent with their potential involvement in NFB activation. Taken together, our observations suggest that PI 3-kinase regulates NFB activation through a novel phosphorylation-dependent mechanism.The transcription factor NFB 1 is activated by interleukin-1 (IL-1), tumor necrosis factor (TNF), and a variety of other stress-inducing stimuli (1-3). In addition to its role in inflammation, NFB has also been implicated in cellular survival, transformation, and oncogenesis (1-3). Predominantly a heterodimeric complex of two polypeptides (p65/RelA and p50), NFB is physically confined to the cytoplasm through its interactions with inhibitors belonging to the IB family of proteins (1-3). When phosphorylated on serine 32 and serine 36, IB␣ is marked and degraded by the ubiquitin/26 S proteasome pathway liberating the NFB heterodimer so that it may translocate to the nucleus. The signaling cascade that induces IB degradation and thus leads to NFB activation has recently been delineated (3). There is compelling evidence that phosphorylation of the regulatory serines on IB␣ is mediated by a 300 -500-kDa multisubunit IB protein kinase (IKK) (4 -10). This kinase complex was purified to apparent homogeneity and shown to be composed primarily of the protein kinases IKK␣ and IKK␤ as well as a protein that lacks a catalytic kinase domain known as IKK␥ (4 -10).The phosphorylation and degradation of IB may not, however, be sufficient to activate NFB. Using two different phosphoinositide 3-kinase (PI 3-kinase) inhibitors, we have previously shown that the PI 3-kinase signaling pathway is also required for NFB activation (11). Whereas wortmannin efficiently blocked IL-1-induced increases in the DNA binding activity of NFB, a domi...

No abstract

Phosphorylation and activation of Akt1 is a crucial signaling event that promotes adipogenesis. However, neither the complex multistep process that leads to activation of Akt1 through phosphorylation at Thr308 and Ser473 nor the mechanism by which Akt1 stimulates adipogenesis is fully understood. We found that the BSD domain–containing signal transducer and Akt interactor (BSTA) promoted phosphorylation of Akt1 at Ser473 in various human and murine cells, and we uncovered a function for the BSD domain in BSTA-Akt1 complex formation. The mammalian target of rapamycin complex 2 (mTORC2) facilitated the phosphorylation of BSTA and its association with Akt1, and the BSTA-Akt1 interaction promoted the association of mTORC2 with Akt1 and phosphorylation of Akt1 at Ser473 in response to growth factor stimulation. Furthermore, analyses of bsta gene-trap murine embryonic stem cells revealed an essential function for BSTA and phosphorylation of Akt1 at Ser473 in promoting adipocyte differentiation, which required suppression of the expression of the gene encoding the transcription factor FoxC2. These findings indicate that BSTA is a molecular switch that promotes phosphorylation of Akt1 at Ser473 and reveal an mTORC2-BSTA-Akt1-FoxC2–mediated signaling mechanism that is critical for adipocyte differentiation.