Re-programming of metabolic pathways is a hallmark of pathological changes in cancer cells. The expression of certain genes that directly control the rate of key metabolic pathways including glycolysis, lipogenesis and nucleotide synthesis is dysregulated for the adaptation and progression of tumor cells to become more aggressive phenotypes. The pentose phosphate pathway controlled by glucose- 6-phosphate dehydrogenase (G6PD) has been appreciated largely to its role as a provider of reducing power and ribose phosphate to the cell for maintenance of redox balance and biosynthesis of nucleotides and lipids. Recently, G6PD has been revealed to be involved in apoptosis, angiogenesis, and the efficacy to anti-cancer therapy, making it as a promising target in cancer therapy. This review summarizes the information about the latest progress relating the activity of the G6PD to cell proliferation, angiogenesis, and resistance to therapy in cancer cells, and discusses the possibility of G6PD as a diagnostic biomarker of cancer and the therapeutic potentials of G6PD inhibitors in cancer treatment. The available data show that G6PD plays a critical role in survival, proliferation, and metastasis of cancer cells. Development of potent and selective G6PD inhibitors would provide novel opportunity for cancer therapy.

It was found that Syk protein-tyrosine kinase is rapidly activated in B cells after H2O2 treatment (oxidative stress) or increased extracellular NaCl concentration (osmotic stress) as well as in response to B cell receptor activation. In this study we examined the involvement of Syk in responses elicited by these types of extracellular stress, particularly Ca2+ responses and c-Jun amino-terminal kinase (JNK) activation, using a chicken B cell line, DT40, as well as the DT40-derived mutant DT40/Syk(-), which does not express Syk. Osmotic stress evokes increases in [Ca2+]i by stimulating an extracellular Ca2+ influx in both DT40 and DT40/Syk(-) cells. In comparison, oxidative stress elicits an increase in [Ca2+]i by stimulating both an extracellular Ca2+ influx and Ca2+ release from internal stores in DT40 cells, but this Ca2+ response is partially abolished in DT40/Syk(-) cells, indicating that the oxidative stress-induced Ca2+ response is at least partly dependent on Syk. Interestingly, the depletion of Ca2+ results in a significantly decreased level of Syk activation in DT40 cells stimulated by oxidative but not osmotic stress. Furthermore, JNK is activated to different extents by these two types of stress. The extent of JNK activation in DT40/Syk(-) cells in response to osmotic stress is comparable to that observed in DT40 cells. Intriguingly, oxidative stress-induced JNK activation is significantly compromised in DT40/Syk(-) cells. Collectively, these results indicate that both the Ca2+ response and JNK activity induced by oxidative stress are partly dependent on Syk, whereas those induced by osmotic stress are independent of Syk.

A chicken B cell line DT40 and its syk-negative or lyn-negative mutants were used to investigate the roles of protein-tyrosine kinases in oxidant $tress signaling. The data presented here for wild-type cells demonstrate that hydrogen peroxide stimulates p53/56""-dependent tyrosine phosphorylation and activation of ~7 2 "~, and induces a rapid and prolonged elevation of intracellular calcium, which consists of calcium release from intracellular stores and influx from the extracellular space. Hydrogen-peroxidetriggered calcium mobilization was impaired in both syk-negative and lyn-negative cells, which was mainly due to the loss of calcium release from intracellular stores. Further studies indicated that inositol trisphosphate production was also abolished in both syk-negative and lyn-negative cells, which is consistent with the loss of calcium release. Taken together, these observations suggest that the defect of ~7 2 " " or p53/56"" was responsible for the abnormality of calcium mobilization in both Zyn-negative and syknegative cells, and that both ~7 2 " '~ and p53/56'"' might regulate calcium mobilization through the phosphatidylinositol pathway in B cell oxidant stress signaling.

The effect of tyrosine phosphorylation of PI3K on its enzymatic activity is quite controversial, and the molecular mechanism by which ROS trigger PI3K membrane relocation is unclear. Therefore, we investigated the regulatory mechanism of hydrogen peroxide-induced PI3K activation in DT40 cells, utilizing genetic and pharmacological approaches. Our results revealed that hydrogen peroxide induced tyrosine phosphorylation of the p110 but not the p85 subunit of PI3K in DT40 cells. This phosphorylation was intact in Btk- and Cbl-deficient DT40 cells, but was drastically suppressed in Lyn, Syk, or BCAP-deficient DT40 cells. Tyrosine phosphorylation of p110 did not alter its catalytic activity, and hydrogen peroxide stimulation did not cause an increase in the intrinsic PI3K activity; however, hydrogen peroxide stimulation did induce PI(3,4,5)P3 accumulation and activate Akt. The activation of Akt, as monitored by its ability to phosphorylate GSK-3alpha/beta and by its S473 phosphorylation, was strictly dependent on PI3K activity. Under our conditions, hydrogen peroxide-induced PI3K and Akt activation was independent of Lyn, Syk, Cbl, BCAP, or Ras when each was eliminated individually either by mutation or by a specific inhibitor. In comparison, Akt activation by B cell receptor cross-linking was dependent on BCAP. In addition, hydrogen peroxide treatment caused an increase in the amount of p85 PI3K associated with the particulate fraction. Together, these results indicate that the hydrogen peroxide-induced PI3K and Akt activation in DT40 cells was achieved through PI3K membrane recruitment to its substrate site, thereby enabling PI3K to maximize its catalytic efficiency.

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Independent of its PPARgamma activity, dPGJ(2) protected cells from oxidative stress by elevating GSH and enhancing MAPK activation. Thus, dPGJ(2) may delay the development of dry-type age-related macular degeneration.

Hydrogen peroxide stimulates a tyrosine kinase-dependent calcium release from intracellular stores, which is assumed to be achieved through the activation of phospholipase Cγ2 (PLCγ2) via a tyrosine phosphorylation mechanism in B cells. Here we show that H 2 O 2 induces both tyrosine phosphorylation on PLCγ2 and the activation of phosphatidylinositol 3-kinase (PI3K) in B cells, and that the phosphatidylinositol 3-kinase inhibitor, Wortmannin, partially inhibited the H 2 O 2 -induced calcium release without affecting tyrosine phosphorylation on PLCγ2. Overexpression of human Bruton's tyrosine kinase (Btk), which was activated by H 2 O 2 , almost completely overcame the inhibition of calcium release by Wortmannin. The reversal of Wortmannin's inhibition by enhancing Btk concentration seemed unique to the H 2 O 2 -mediated effect, because Btk failed to overcome the inhibition of Wortmannin on B cell receptor-triggered calcium mobilization. Immunoblot analysis revealed that Btk formed stable complexes with several tyrosine-phosphorylated proteins, including PLCγ2, only in Btk-overexpressed cells on H 2 O 2 stimulation. Together, our data are consistent with the notion that PIP3 and/or a high concentration of Btk target the activated PLCγ2 to its substrate site for maximal catalytic efficiency.

Agonists of retinoid X receptors (RXRs), which include the natural 9-cis-retinoic acid and synthetic analogs, are potent inducers of growth arrest and apoptosis in some cancer cells. As such, they are being used in clinical trials for the treatment and prevention of solid tumors and are used to treat cutaneous T cell lymphoma. However, the molecular mechanisms that underlie the anticancer effects of RXR agonists remain unclear. Here, we show that a novel pro-apoptotic pathway that is induced by RXR agonist is negatively regulated by casein kinase 1␣ (CK1␣). CK1␣ associates with RXR in an agonist-dependent manner and phosphorylates RXR. The ability of an RXR agonist to recruit CK1␣ to a complex with RXR in cells correlates inversely with its ability to inhibit growth. Remarkably, depletion of CK1␣ in resistant cells renders them susceptible to RXR agonist-induced growth inhibition and apoptosis. Our study shows that CK1␣ can promote cell survival by interfering with RXR agonist-induced apoptosis. Inhibition of CK1␣ may enhance the anti-cancer effects of RXR agonists.