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PubMed2005

Targeted agents for the treatment of advanced renal cell carcinoma.

Renal cell carcinoma (RCC) is a highly treatment-resistant tumor type; however, advances in elucidating the molecular pathophysiology underlying RCC has led to the identification of promising targets for therapeutic intervention. In clear-cell RCC, mutations to the von Hippel-Lindau (VHL) gene results in the up regulation of many proteins necessary for tumor growth and survival--such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and platelet derived growth factor (PDGF), which are involved in tumor-initiated angiogenesis. Carbonic anhydrase IX and signaling via the epidermal growth factor receptor (EGFR) are involved in tumor cell proliferation and are also up regulated by mutation in the VHL gene. The intracellular messenger pathways phosphoinositide 3-kinase (PI3K) and Raf/MEK/ERK act as convergence points for positive growth signaling; the Raf/MEK/ERK pathway is also implicated in apoptosis. Several agents in development target VEGF (bevacizumab), the VEGF receptor (PTK787, SU11248, VEGF-trap, and BAY 43-9006), the PDGF receptor (SU11248 and BAY 43-9006), or the EGF receptor (gefitinib, cetuximab, ABX-EGF, and erlotinib). The intracellular Raf/MEK/ERK signaling cascade has been targeted at either the level of Raf (BAY 43-9006, ISIS 5132) or MEK (CI-1040, PD184352 and ARRY-142886), and PI3K signaling is disrupted by CCI-779. WX-G250 targets the G250 antigen, and PS-341 disrupts the 26S proteasome mediating the degradation of intracellular proteins. Given that multiple pathways contribute to tumor growth, anti-tumor activity may be increased by agents targeting multiple pathways, or by combining agents to allow horizontal or vertical inhibition of multiple pathways.

Angiogenesis Inhibitors↗
PubMed2004

Phosphatidylinositol 3-kinase is a determinant of responsiveness to B cell antigen receptor-mediated Epstein-Barr virus activation.

B cell Ag receptor (BCR) cross-linking with anti-Ig Abs efficiently induces activation of latently infected EBV in some B cell lines, but not in others. The present study was aimed at defining the molecular mechanisms that determine the response to BCR-mediated EBV activation. Comparison of Burkitt's lymphoma-derived Akata, Mutu-I, and Daudi cells, which are representative responders and nonresponders to BCR-mediated EBV activation, respectively, indicated that three signaling pathways, phosphatidylinositol 3-kinase (PI3K), extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein kinase (MAPK), were activated in anti-Ig-treated Akata and Mutu-I cells. However, in anti-Ig-treated Daudi cells PI3K was not activated, ERK was faintly activated, and p38 MAPK was constitutively phosphorylated irrespective of anti-Ig treatment. Restoration of PI3K activity with insulin-like growth factor 1 restored ERK and p38 MAPK pathways, and was accompanied by EBV activation in anti-Ig-treated Daudi cells. In contrast, a specific inhibitor for PI3K, wortmannin, inhibited EBV activation by anti-Ig Abs in Akata and Mutu-I cells. Transfection assays in EBV-negative Daudi cells revealed that PI3K activated a promoter for BZLF1, which is a switch of EBV activation from a latent infection, in the absence of other EBV products suggesting that the BZLF promoter was a target of BCR signaling, and that PI3K was important for BCR-mediated BZLF1 activation. These results indicate that the absence of PI3K impedes the progression of signals through the BCR and becomes a determinant of unresponsiveness to BCR-mediated EBV activation.

Antibodies, Anti-Idiotypic↗
PubMed2002

Regulation of cell size in growth, development and human disease: PI3K, PKB and S6K.

It has generally been observed that cells grow to a certain size before they divide. In the last few years, the PI3K signal transduction pathway has emerged as one of the main signaling routes utilized by cells to control their increase in size. Here we focus on two components of this pathway, PKB and S6K, and briefly review the experiments that initially uncovered their roles in cell size control. In addition, we discuss a number of recent observations suggesting that the generic models used to describe this pathway to date may have been oversimplified. Indeed, recent observations in Drosophila and mouse support a more complex interaction between these signaling components in development. Finally, we have utilized two contemporary studies involving PKB- and S6K-deficient mice as a paradigm to underscore the importance of cell size and to accurately delineate the connections between signaling pathways for human disease, such as diabetes mellitus.

Animals↗
PubMed2026

Oncogenic Mutations and Tumor Microenvironment Alterations in Diffuse Large B-Cell Lymphoma With Bulky Disease.

BACKGROUND: Bulky disease represents a clinically aggressive subset of diffuse large B-cell lymphoma (DLBCL) associated with adverse clinical outcomes. The aim of this study was to investigate the influence of oncogenic mutations and tumor microenvironment alterations on bulky disease in DLBCL. METHODS: We analyzed a cohort of 939 patients with newly diagnosed DLBCL. Using DNA (n = 934) and RNA (n = 524) sequencing, we compared oncogenic mutations and tumor microenvironment (TME) alterations based on tumor diameter, with cutoff values at 5.0 cm and 10.0 cm. Further stratification by mutations in key genes (CD58, STAT6, EBF1) correlated with tumor diameter revealed distinct transcriptomic and immunologic profiles. Subsequent single-cell RNA sequencing, guided by these mutational signatures, resolved the cellular heterogeneity within the TME. RESULTS: Integrative analysis revealed that tumor diameter correlated with increased incidence of mutations in CD58, STAT6, and EBF1; adverse genetic subtypes such as EZB-like MYC+ and TP53Mut; activation of oncogenic pathways (JAK/STAT, BCR, PI3K, and MYC); and an immunosuppressive tumor microenvironment. Notably, immune checkpoint molecules varied across the bulky stages, with CTLA-4, TIGIT, ICOS, and CD28 expression inversely correlated with tumor diameter, while CD70 and 4-1BBL expression positively correlated. Single-cell RNA sequencing further revealed mutation-specific tumor microenvironment insights. CD58-mutated tumor exhibited a profoundly immune-deserted microenvironment dominated by malignant B cells with minimal immune infiltration, whereas STAT6-mutated tumor was associated with increased fibroblasts and CD4 + T cells, particularly regulatory T cells (Treg) and Th1-like cells; EBF1-mutated tumor was characterized by increased proportions of malignant B cells. CONCLUSIONS: Collectively, our findings highlight the biological complexity of bulky disease, identifying candidate molecular targets and providing a biological framework for future therapeutic hypothesis generation in this clinically aggressive subset of DLBCL.

Humans↗
PubMed2005

Alternative splicing of MDM2 mRNA in lung carcinomas and lung cell lines.

The MDM2 gene is overexpressed in several human tumors and its product may be processed into various isoforms. Recently, alternative splicing forms of MDM2 mRNA have been detected in various types of tumors. In this study, lung tissue from human non small cell lung cancers was examined for MDM2 mRNA splicing variants by nested RT-PCR. Of the 117 lung cancer tissue samples analyzed, a total of 31 (26.5%) had splice variants for the MDM2 gene, while 59 (50.4%) had undetectable levels of MDM2 transcript. Further analysis indicated that the predominant variant for 26 of the 31 samples with alternative MDM2 splicing products was MDM2-657, a splice variant lacking exons 3-11. Significant associations were found between the frequency of alternative splicing and the gender and smoking habits of the patients. Approximately 36% of male patients had alternative splicing of MDM2 compared with only 9.5% of female patients (P = 0.008); 44.2% of the smoker patients had alternative MDM2 splice forms versus 16.2% of nonsmokers (P = 0.003). Furthermore, most normal lung cell lines examined possessed only full-length MDM2 mRNA, while among several lung cancer cell lines, only H1355 and CaLu-1 cells lacked alternatively spliced MDM2 transcripts. When H1355 cells were treated in vitro with the cigarette smoke carcinogen benzo[a]pyrene (B[a]P) or the B[a]P metabolite benzo[a]pyrene diolepoxide (BPDE), three MDM2 splicing products were detected by nested RT-PCR. Finally, with the use of several specific inhibitors, we found that BPDE-induced MDM2 mRNA alternative splicing in H1355 cells may occur through the PI3K or MAPK pathway. Overall, our results suggest that carcinogens present in cigarette smoke increase the risk of alternative MDM2 splicing, which is highly associated with lung cancer.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2006

Elucidating the role of protein kinase C in chronic lymphocytic leukaemia.

While advances have been made in the clinical treatment of chronic lymphocytic leukaemia (CLL) in recent years, it is still an incurable disease and therefore the identification of novel drug therapies is of paramount importance. Understanding the molecular mechanisms that govern the survival of CLL cells is fundamental in achieving this goal. A number of studies indicate that protein kinase C (PKC)- and phosphatidylinositol-3-kinase (PI3K)- mediated signalling pathways are central to CLL cell survival, and as such PKC has gained renewed interest as a potential drug target in CLL. This may be because it represents a closely-related family of ten protein kinases, which due to the redundancy that exists between isoforms offers an opportunity for the design of isoform specific inhibitors drugs that target leukaemic cells whilst showing reduced toxicity for normal cells. Indeed, PKC signalling pathways have already been considered as targets for specific anticancer drugs [1-3]. Therefore, this short review will focus on the effect of modulating PKC activity in CLL cells and explore whether targeting PKCs could represent a valid therapy for this leukaemia.

Cell Survival↗
PubMed2006

In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer.

Mammalian target of rapamycin (mTOR) is considered to be a major effector of cell growth and proliferation that controls protein synthesis through a large number of downstream targets. We investigated the expression of the phosphatidylinositol 3'-kinase (PI3K)/mTOR signaling pathway in human pancreatic cancer cells and tissues, and the in vivo antitumor effects of the mTOR inhibitor CCI-779 with/without gemcitabine in xenograft models of human pancreatic cancer. We found that the Akt, mTOR and p70 S6 kinase (S6K1) from the PI3K/mTOR signaling pathway were activated in all of the pancreatic cancer cell lines examined. When surgically resected tissue specimens of pancreatic ductal adenocarcinoma were examined, phosphorylation of Akt, mTOR and S6K1 was detected in 50, 55 and 65% of the specimens, respectively. Although CCI-779 had no additive or synergistic antiproliferative effect when combined with gemcitabine in vitro, it showed significant antitumor activity in the AsPC-1 subcutaneous xenograft model as both a single agent and in combination with gemictabine. Furthermore, in the Suit-2 peritoneal dissemination xenograft model, the combination of these 2 drugs achieved significantly better survival when compared with CCI-779 or gemcitabine alone. These results demonstrate promising activity of the mTOR inhibitor CCI-779 against human pancreatic cancer, and suggest that the inhibition of mTOR signaling can be exploited as a potentially tumor-selective therapeutic strategy.

Adenocarcinoma↗
PubMed2002

IGF-1 induces Pin1 expression in promoting cell cycle S-phase entry.

Insulin-like growth factor I (IGF-1) is a well-established mitogen to many different cell types and is implicated in progression of a number of human cancers, notably breast cancer. The prolyl isomerase Pin1 plays an important role in cell cycle regulation through its specific interaction with proteins that are phosphorylated at Ser/Thr-Pro motifs. Pin1 knockout mice appear to have relatively normal development yet the Pin1(-/-)mouse embryo fibroblast (MEF) cells are defective in re-entering cell cycle in response to serum stimulation after G0 arrest. Here, we report that Pin1(-/-) MEF cells display a delayed cell cycle S-phase entry in response to IGF stimulation and that IGF-1 induces Pin1 protein expression which correlates with the induction of cyclin D1 and RB phosphorylation in human breast cancer cells. The induction of Pin1 by IGF-1 is mediated via the phosphatidylinositol 3-kinase as well as the MAP kinase pathways. Treatment of PI3K inhibitor LY294002 and the MAP kinase inhibitor PD098059, but not p38 inhibitor SB203580, effectively blocks IGF-1-induced upregulation of Pin1, cyclin D1 and RB phosphorylation. Furthermore, we found that Cyclin D1 expression and RB phosphorylation are dramatically decreased in Pin1(-/-) MEF cells. Reintroducing a recombinant adenovirus encoding Pin1 into Pin1(-/-) MEF cells restores the expression of cyclin D1 and RB phosphorylation. Thus, these data suggest that the mitogenic function of IGF-1 is at least partially linked to the induction of Pin1, which in turn stimulates cyclin D1 expression and RB phosphorylation, therefore contributing to G0/G1-S transition.

Cyclin D1↗
PubMed2005

Phosphoinositide 3-kinase/Akt involvement in arsenic trioxide resistance of human leukemia cells.

The purpose of this study was to evaluate the possible involvement of the phosphoinositide 3-kinase (PI3K)/Akt survival pathway in determining resistance to arsenic trioxide (As2O3)-induced apoptosis. We employed a HL60 cell clone (HL60AR) with a constitutively active PI3K/Akt survival pathway, as well as U937 and K562 cells. In addition, we used parental (PT) HL60 cells overexpressing a constitutively active Akt. Selective pharmacological inhibitors of the PI3K/Akt axis (LY294002, wortmannin) were employed to influence the sensitivity to As2O3. While HL60PT cells were sensitive to 2.5 microM As2O3 and died of apoptosis, HL60AR cells were resistant up to 5 microM As2O3. Treatment with either LY294002 or wortmannin lowered resistance of HL60AR cells to As2O3. Also in U937 and K562 cells, inhibitors of the PI3K/Akt axis caused a decrease in As2O3 resistance. Overexpression of constitutively active Akt in HL60PT cells caused the induction of resistance to 2.5 microM As2O3. Conversely, forced expression of a dominant negative Akt in HL60AR cells resulted in a decrease in As2O3 resistance. Moreover, HL60 cell resistance to 2.5 microM As2O3 could be significantly reduced by incubation with SN50, a peptide inhibitor selective for the NF-kappaB transcription factor. Taken together our findings suggest that a constitutive activation of the PI3K/Akt pathway, which is increasingly detected in some types of acute myeloid leukemia, may contribute to As2O3 resistance, most likely through NF-kappaB activation. Selective pharmacological inhibitors of this survival pathway, as well as of NF-kappaB, might be usefully employed in the future to reverse resistance to this treatment.

Androstadienes↗
PubMed2006

Increased sensitivity to the platelet-derived growth factor (PDGF) receptor inhibitor STI571 in chemoresistant glioma cells is associated with enhanced PDGF-BB-mediated signaling and STI571-induced Akt inactivation.

The platelet-derived growth factor receptor (PDGFR) is a tyrosine kinase, implicated in the development and progression of different tumors, including gliomas. Chemoresistance is a common feature of malignant gliomas. Since receptor tyrosine kinases contribute to chemoresistance in tumors, we addressed whether PDGFR signaling might confer selective growth advantage to chemoresistant cells. The effects of the PDGFR inhibitor STI571 on proliferation and PDGFR signaling were compared in chemosensitive and cisplatin-selected, chemoresistant sublines derived from glioma and from two other PDGFR-expressing tumors (ovarian carcinoma and neuroblastoma). The chemoresistant glioma U87/Pt cells were twofold more sensitive to STI571 growth-inhibitory effects than the chemosensitive U87 cells, and two- to threefold more sensitive than five unrelated glioma cell lines. The other two paired cell lines were equally responsive. Sensitization of U87/Pt cells correlated with upregulation of the PDGF-B isoform and with PDGF-BB-induced Akt overactivation, which was prevented by STI571. STI571 specifically inhibited PDGF-BB-, but not PDGF-AA- or stem cell factor-mediated signaling. In serum-containing medium, STI571 decreased phospho-Akt in U87/Pt cells, but not in U87, while activating extracellular signal-regulated kinase (Erk) in both. STI571 antiproliferative effects were partially reverted by constitutively active Akt. Cotreatment with inhibitors of phosphatidylinositol 3'-kinase (PI3K) or mitogen-activated protein kinase kinase (MEK) resulted in enhanced growth inhibition in glioma cells. Our results suggest that increased PDGF-BB signaling may sensitize chemoresistant glioma cells to STI571, suggesting a therapeutic potential for STI571 in patients with malignant gliomas refractory to chemotherapy. Simultaneous blockade of PDGFR and PI3K or Erk pathway may enhance therapeutic targeting in gliomas.

Antineoplastic Agents↗
PubMed1998

Modulation of the vascular smooth muscle angiotensin subtype 2 (AT2) receptor by angiotensin II.

The angiotensin subtype 2 (AT2) receptor is scarce in most adult vascular tissues except after injury. Since angiotensin II (AngII) is released upon injury, we examined the possibility that AngII governs AT2 receptor expression in smooth muscle cells (SMC). A polyclonal antiserum, raised to a peptide corresponding to the AT2 receptor C-terminus, recognized a approximately 45-kDa protein after transfection of cos-7 cells with AT2 receptor cDNA. Detection of a approximately 65-kDa band in extracts of SMC indicated that the AT2 receptor was glycosylated. Treatment of SMCs with AngII increased AT2 receptor levels fourfold over 24 h. This response was abrogated by losartan, but not by PD123319, indicating AT1 receptor involvement. AngII-dependent increases in AT2 receptor levels were also prevented by LY294002, an inhibitor of phosphatidyinositol 3-kinase, but not by rapamycin. These results indicate AngII influences AT2 receptor expression through the AT1 receptor via a signaling pathway that includes PI3K.

Angiotensin II↗
PubMed2001

Pertussis toxin activates tyrosine kinase signaling cascade in myelomonocytic cells: a mechanism for cell adhesion.

Pertussis toxin (PTX) has recently been shown to specifically bind to CD14 to promote myelomonocytic cell adhesion to serum. The present study investigated the signaling mechanisms responsible for PTX-induced differentiated U937 cell adhesion. PTX-induced myelomonocytic cell adhesion was blocked by genistein or tyrphostin-47 (two protein tyrosine kinase inhibitors), LY294002 (a phosphatidylinositol 3-kinase (PI3K) inhibitor), or PD098059 (a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor). PTX induced a rapid tyrosine phosphorylation of several discrete cytoplasmic proteins, which could be inhibited by genistein or tyrphostin 47. In addition, PTX induced phosphorylation of Akt and of ERK2, which could be completely blocked by LY294002 and PD098059, respectively, and by genistein or tyrphostin 47 as well. All of these PTX-induced signaling events could be reproduced using purified PTX B-oligomer (PTX-B) alone. Our data show that PTX can activate tyrosine kinase signaling cascade, including the downstream PI3K and ERK/MAPK pathways, in myelomonocytic cells to induce cell adhesion to serum.

Cell Adhesion↗
PubMed2000

Life and death decisions in B1 lymphoma cells.

Crosslinking of surface immunoglobulin (Ig) receptors with anti-IgM (anti-mu) but not anti-IgD (anti-delta) antibodies causes growth arrest and apoptosis in several extensively characterized B1-like lymphoma cell lines. While anti-mu stimulates a transient increase in c-myc mRNA and protein expression, followed by a rapid decline below the baseline level, anti-delta only causes a moderate increase in the expression of this oncogene, which returns to baseline levels within 24-48 hours. However, signals downstream from anti-delta can be converted into an apoptotic pathway by modulating PI3K activity, suggesting that PI3K is a critical rheostat controlling survival signals in B1 cell lines. Anti-mu-induced down-regulation of c-Myc is followed in time with an increase in the cyclin dependent kinase inhibitor, p27Kip1, in all anti-mu sensitive lymphoma lines. This increase correlates with growth arrest and apoptosis. The anti-mu-mediated decrease in c-Myc, increase in p27Kip1, growth arrest and apoptosis, can all be prevented via CD40/CD40L signaling. Inhibition of caspase activation, on the other hand, prevents anti-mu-induced apoptosis, but has no effect on c-Myc, p27Kip1, and G1 arrest. Interestingly, we also found that steroids and retinoids can mimic anti-mu-mediated signaling and lead to a loss of c-Myc, an increase in p27Kip1, G1 arrest, and apoptosis. Together, these data suggest that modulation of c-Myc and p27Kip1 protein levels is crucial for the life versus death decisions in murine immature B1-like lymphoma cells lines.

Antibodies, Anti-Idiotypic↗
PubMed2005

Activation of glycogen synthase kinase-3 induces Alzheimer-like tau hyperphosphorylation in rat hippocampus slices in culture.

Formation of neurofibrillary tangle from hyperphosphorylated tau is one of the hallmark lesions seen in Alzheimer's disease (AD) brain, and neuronal deregulation of glycogen synthase kinase-3 (GSK-3) activity plays key role in tau hyperphosphorylation. In the present study, the role of GSK-3 on tau phosphorylation in hippocampus slice culture was examined by incubating the slice with wortmannin (WT), an inhibitor of phosphatidylinositol 3-kinase (PI3K) and GF-109203X (GFX), an inhibitor of protein kinase C (PKC). It was found that treatment of the slices with GFX or WT separately induced tau hyperphosphorylation both at Ser396/Ser404 (PHF-1) and Ser199/Ser202 (Tau-1) sites. The phosphorylation rate of tau at PHF-1 and Tau-1 epitopes was further increased when GFX and WT were used in combination, and at this condition, AD-like tau accumulation was observed. GSK-3 activity was significantly increased with a concurrently decreased level of inactivated form of GSK-3. Lithium chloride (LiCl), a GSK-3 inhibitor, prevented tau from WT- and GFX-induced hyperphosphorylation. It suggests that GSK-3 is regulated through PI3K and PKC pathway, and activation of GSK-3 not only induces hyperphosphorylation of tau but also leads to accumulation of tau in cultured rat brain slice.

Alzheimer Disease↗
PubMed2004

Integrin-linked kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition.

The role of integrin-linked kinase (ILK) in transforming growth factor beta (TGFbeta)-mediated epithelial to mesenchymal transition was investigated. A stable transfection of dominant-negative ILK results in the prevention of TGFbeta-mediated E-cadherin delocalization. TGFbeta-mediated phosphorylation of Akt at Ser-473 was inhibited by dominant-negative ILK and PI3K inhibitors, LY294002 and wortmannin. Treatment with TGFbeta stimulated induction of Akt and ILK kinase activity in HaCat control cells. This increased ILK activity by TGFbeta was lowered by PI3K inhibitor, LY294002. In addition, PI3K inhibitor, dominant-negative Akt, and dominant-negative ILK could not block TGFbeta-mediated C-terminal phosphorylation of Smad2. Taken together, these data suggest that PI3K-ILK-Akt pathway that is independent of the TGFbeta-induced Smad pathway is required for TGFbeta-mediated epithelial to mesenchymal transition.

Cell Differentiation↗
PubMed2004

Surviving the kiss of death.

Executioner caspases induce the biochemical and cellular changes characteristic of apoptosis. Activation of caspases is therefore regarded as "the kiss of death" resulting in the cell's demise. Recent reports indicate however that in some situations, caspase activation may induce other responses than apoptosis. These findings raise the question of how cells manage to counteract the killing activities of executioner caspases. Experiments performed in our laboratory have unraveled a mechanism that allows cells to survive in the presence of activated executioner caspases. This mechanism is based on the partial cleavage of RasGAP into an N-terminal fragment that activates the Ras-PI3K-Akt survival pathway. This protective pathway may be activated to allow cells to use executioner caspases for other purposes than inducing apoptosis.

Animals↗
PubMed2004

Molecular mechanisms of deguelin-induced apoptosis in transformed human bronchial epithelial cells.

Increasing evidence has demonstrated that the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway plays an important role in cell proliferation, apoptosis, angiogenesis, adhesion, invasion, and migration, functions that are critical to cancer cell survival and metastasis. Increased expression of activated Akt has been observed in the early stages of tobacco-induced lung carcinogenesis. Moreover, blocking the PI3K/Akt pathway specifically inhibits the proliferation of non-small cell lung cancer (NSCLC) cells, indicating that the PI3K/Akt pathway is a potential target for chemoprevention and therapy in lung cancer. The aim of this work is to study the lung cancer chemopreventive potential of PI3K/Akt inhibitors using an in vitro lung carcinogenesis model. We found that genetic or pharmacologic approaches targeting the PI3K/Akt pathway inhibited the proliferation of premalignant and malignant human bronchial epithelial (HBE) cells. After screening several natural products to identify a potential lung cancer chemopreventive agent, we have found that deguelin, a rotenoid isolated from Mundulea sericea (Leguminosae), specifically inhibits the growth of transformed HBE and NSCLC cells by inducing cell-cycle arrest in the G2/M phase and apoptosis, with no detectable toxic effects on normal HBE cells, most likely due to the agent's ability to inhibit PI3K/Akt-mediated signaling pathways. The specific sensitivity of premalignant and malignant HBE and NSCLC cells to deguelin suggests that this drug could be clinically useful for chemoprevention in early-stage lung carcinogenesis and for therapy in confirmed lung cancer.

Apoptosis↗
PubMed2005

Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance.

While tumors become addicted to oncogenes like Ras, the microenvironment in which tumor cells reside changes during tumorigenesis; the cells are surrounded initially by normal tissue and later by tumor tissue. Hence, we asked if Ras exerts its oncogenic effects through the same set of effectors during different stages of tumorigenesis. We now show in human cells that the Ras effector pathways MAPK, RalGEF, and PI3K are required to initiate tumor growth. Conversely, activation of the PI3K/AKT pathway replaced Ras once tumors formed, although other effectors were still activated independently of Ras, presumably by factors provided upon the establishment of a tumor microenvironment. Thus, as tumorigenesis progresses the addiction of cancers to their initiating oncogene is reduced to, at least in the case of Ras, the PI3K/AKT pathway.

Animals↗