Kegg Pathway: Apoptosis

Int J Cancer. 2009 Nov 18;
Bhattacharya N, Sarno A, Idler IS, Führer M, Zenz T, Döhner H, Stilgenbauer S, Mertens D

Contemporary research on cellular signaling has undergone a shift of focus from qualitative measurements of single signaling pathways to high-throughput quantitation of comprehensive signaling networks. Notably, NFkappaB is a family of transcription factors involved in immune and inflammatory responses, developmental processes, cellular growth and Apoptosis, and is deregulated in a number of disease states. We have established a chemiluminescent oligonucleotide-based ELISA (co-ELISA) that is simple and quantitative. In contrast to currently used assays, it allows quantitation of all NFkappaB components (i.e. RelA, p50, p52, RelB, and c-Rel). In addition, it can make use of whole extract and does not require cumbersome nuclear/cytosolic fractionation, saving time and resources. Co-ELISA has a 3.5- to 43-fold higher signal-over-noise ratio than currently available assays, while the percent relative standard deviation is 3-to 6-fold lower. Also, the novel method is faster than EMSA, not restricted to transfectable cells as is the case for luciferase reporter assays, and ten times more cost-efficient than commercially available ELISA assays. Co-ELISA is a sensitive, fast, and cost-efficient quantitation method for all DNA-binding NFkappaB proteins that can be used in high-throughput experimentation. (c) 2009 UICC.

Small. 2009 Nov 18;
Song WJ, Du JZ, Sun TM, Zhang PZ, Wang J

An efficient and safe delivery system for small interfering RNA (siRNA) is required for clinical application of RNA interfering therapeutics. Polyethyleneimine (PEI)-capped gold nanoparticles (AuNPs) are successfully manufactured using PEI as the reductant and stabilizer, which bind siRNA at an appropriate weight ratio by electrostatic interaction and result in well-dispersed nanoparticles with uniform structure and narrow size distribution. With siRNA binding, PEI-capped AuNPs induce more significant and enhanced reduction in targeted green fluorescent protein expression in MDA-MB-435s cells, though more internalized PEI/siRNA complexes in cells are evidenced by confocal laser scanning microscopy observation and fluorescence-activated cell sorting analyses. PEI-capped AuNPs/siRNA targeting endogenous cell-cycle kinase, an oncogene polo-like kinase 1 (PLK1), display significant gene expression knockdown and induce enhanced cell Apoptosis, whereas it is not obvious when the cells are treated with PLK1 siRNA using PEI as the carrier. Without exhibiting cellular toxicity, PEI-capped AuNPs appear to be suitable as a potential carrier for intracellular siRNA delivery.

Histol Histopathol. 2010 Jan; 25(1): 21-32
D'Emilio A, Biagiotti L, Burattini S, Battistelli M, Canonico B, Evangelisti C, Ferri P, Papa S, Martelli AM, Falcieri E

Some neuromuscular disorders, such as Duchenne muscular dystrophy, hereditary inclusion body myopathy, malignant hyperthermia, alcoholic myopathy and mitochondrial myopathies are characterized by oxidative stress and loss of muscle fibres due to Apoptosis. In this study we have analyzed muscle cell death in vitro utilizing C2C12 myoblasts and myotubes, inducing Apoptosis by means of UVB irradiation. C2C12 cells were analysed by scanning and transmission electron microscopy (SEM, TEM) as well as by TUNEL reaction. DNA analysis was performed by gel electrophoresis and flow cytometry. MitoTracker red CMXRos and JC-1 fluorescent probes were also used to study mitochondrial behavior. Finally, caspase activity was investigated by means of Western blot, while caspase-9 and -3 inhibitor effects by means of SEM. SEM showed the typical membrane blebbing while TEM revealed the characteristic chromatin condensation. The TUNEL reaction presented a certain positivity too. Apoptotic and non-apoptotic nuclei in the same myotube were identified both by TUNEL and TEM. Gel electrophoresis never showed oligonucleosomal DNA fragmentation, in agreement with the cell cycle analysis performed by flow cytometry which did not reveal a sharp subdiploid peak. Mitochondrial response to UVB was later investigated and a decrease in mitochondrial functionality appeared. Caspase-9 and -3 cleavage, and, consequently, the activation of the caspase cascade, was also demonstrated by Western blot. Moreover a decrease in apoptotic cell number was noted after caspase-9 and-3 inhibitor treatment. All these results indicated that UVB irradiation induces Apoptosis, both in myoblasts and in myotubes, the second being more resistant. DNA fragmentation, at least the nucleosomic type, does not occur. A certain double-strand cleavage appears in TUNEL analysis, as well as characteristic ultrastructural changes in chromatin.

Med Oncol. 2009 Nov 19;
Liao F, Dong W, Fan L

Hepatoma-derived growth factor (HDGF) is a novel multifunctional growth factor that elicits pleiotropic effects on biological processes such as lung remodeling and renal development. Recent studies demonstrated that HDGF is related to tumor proliferation, invasion, angiogenesis, and Apoptosis. However, the molecular mechanism of HDGF's involvement in Apoptosis remains to be clarified. In this study, we first analyze the role of HDGF in colorectal carcinoma (CRC) progression by immunohistochemistry. Then we used small interference RNA (HDGF-siRNA) to block HDGF and assessed its effect on inducing Apoptosis of CRC loVo cells. Apoptosis was detected using flow cytometry (FCM), DNA ladder analysis, and Hoechst 33258 staining. In addition, the expression levels of some Apoptosis-related proteins were examined by western blot. The result showed that HDGF expression gradually increased in the colorectal carcinogenesis process. Further studies demonstrated that knock-down of HDGF can down-regulate the survivin, activate the mitochondrial pathway, and induce Apoptosis in loVo cells. These findings suggest that HDGF is involved in colorectal carcinogenesis process. Further blocking HDGF exhibits potent pro-apoptotic properties in colon cancer cells. Thus, HDGF might be a potential therapeutic target for human colorectal cancer. These findings may have major implications in the treatment of colorectal cancer.

Neurotox Res. 2009 Nov 19;
Lopes MA, Meisel A, Carvalho FD, de Lourdes Bastos M

Doxorubicin (DOX) is neurotoxic to serum-free cultures of rat cortical neurons in a biphasic concentration manner. For concentrations up to 0.5 muM, cell death follows an apoptotic pattern, while for higher concentrations Apoptosis is inhibited and necrosis becomes dominant. Considering the potential toxic effects of DOX resulting from its redox-cycling, in this study we investigated the generation of reactive species and subsequent oxidative stress effects, formation of quinoproteins, activation of NF-kB, depletion of energy levels and consequent cell death in cultures of primary rat cortical cells challenged with this antitumour drug. The influence of neuronal nitric oxide synthase (nNOS) on DOX-induced neuronal cell damage was subsequently evaluated. The exposure of rat cortical primary cell cultures to DOX resulted in a significant generation of ROS/RNS, activation of NF-kB, depletion of GSH levels, depletion of ATP, and cell death, in a concentration biphasic manner. Doxorubicin also significantly increased protein-bound quinone products in neurons in a concentration-dependent manner. Inhibition of nNOS decreased neuronal cell death induced by DOX in a significant way, at the first phase of the biphasic curve. In conclusion, this study shows, for the first time, a clear involvement of nNOS and subsequent ROS/RNS generation as crucial signalling mediators of DOX-induced neurotoxicity on isolated cortical neurons. Inhibition of ROS/RNS formation, modulation of NOS isoforms and modulation of NF-kB activation could be of beneficial in preventing damage in the CNS caused by DOX.

J Cancer Res Clin Oncol. 2009 Nov 19;
Wellmann A, Fogt F, Hollerbach S, Hahne J, Koenig-Hoffmann K, Smeets D, Brinkmann U

PURPOSE: The deleted-in-polyposis1-like1 (DP1L1) gene displays pro-apoptotic activity and was proposed to be a tumor suppressor. It locates on chromosome 19p13.3, which harbors the locus for Peutz-Jeghers-Syndrome and is deleted in various tumors. We analyzed the association of DP1L1 polymorphisms with colon cancer, and cancer-associated Ulcerative colitis and Crohn's disease. EXPERIMENTAL DESIGN: Fifty-eight patients with colon cancer, 18 with Ulcerative colitis, 18 with Crohn's disease, and 70 control individuals were genotyped for SNPs at positions 992 and 996 of DP1L1 cDNA. RESULTS: Homozygous carriers of 992A alleles comprised 16% of the control group but were significantly increased in colon cancer with a frequency of 36% (P = 0.013 cancer vs control). Homozygous 991-A was also elevated in Ulcerative colitis (N = 18) with a frequency of 33%. In contrast, 18 patients with Crohn's disease showed no difference in frequency of 992AA (22%) compared to control. The A-allele of the adjacent C996A polymorphism has a low frequency (3.5%) in the control population, but significantly increased frequency of 13% in colon cancer (P = 0.0149 for allele frequency, Fisher's exact). 996-A allele frequency is also increased in inflammatory bowel disease (IBD): 22% of Ulcerative colitis- and 50% of Crohn's disease-patients were heterozygous carriers of 996-A (P = 0.052 for CU and P < 0.0001 for MC vs controls). CONCLUSIONS: DP1L1 polymorphisms are associated with colon cancer and IBD. This indicates that DP1L1 plays a functional role in these conditions. Thus DP1L1 may be a diagnostic and therapeutic target for colon cancer and IBD.

Intensive Care Med. 2009 Nov 19;
Lerolle N, Nochy D, Guérot E, Bruneval P, Fagon JY, Diehl JL, Hill G

PURPOSE: Septic shock is one of the leading causes of acute kidney injury. The mechanisms of this injury remain mostly unknown notably because of the lack of data on renal histological lesions in humans. METHODS: Kidney biopsy was performed immediately post-mortem in consecutive patients who died of septic shock. Comparisons were made with specimens from eight patients who died of trauma on scene and nine ICU patients that died of non-septic causes. RESULTS: Nineteen septic patients were included, 11 were male, and age was 72 +/- 12 years. Anuria occurred in all patients 2.2 +/- 1.4 days before death. Seven patients had disseminated intravascular coagulation. In all patients we observed (1) acute tubular lesions whose intensity correlated with blood lactate concentration; (2) intense infiltration by leukocytes, mainly monocytic, in glomeruli and interstitial capillaries as compared to controls; (3) presence of tubular cell Apoptosis proved by the presence of apoptotic bodies (2.9% of tubular cells) significantly more frequently than in controls and confirmed by TUNEL and activated caspase-3 staining. Arteriolar/arterial thromboses were observed in only 4 of 19 patients, without any association with presence of disseminated intravascular coagulation. CONCLUSIONS: Kidney lesions in septic shock go beyond those associated with simple acute tubular injury, notably capillary leukocytic infiltration and Apoptosis. Vascular thrombosis, however, did not appear to play a major role in the majority of patients. The extent to which these lesions are specific to sepsis or are common to all multi-organ failure independent of its cause is yet to be elucidated.

Intensive Care Med. 2009 Nov 19;
Joannes-Boyau O, Honoré PM, Boer W, Rose T

Clin Exp Med. 2009 Nov 19;
Liu Y, Gao W, Zhang D

Smoking is a risk factor for idiopathic pulmonary fibrosis (IPF), but the mechanism of the association remains unknown. The aim of this study was to investigate the effects of cigarette smoke extract (CSE) on A549 cells and human lung fibroblasts treated with transforming growth factor-beta1. A transwell two-chamber coculture system was used to study the proliferation, differentiation, morphologic changes and soluble factors production of A549 cells and myofibroblasts. Low concentrations of CSE promoted myofibroblasts proliferation; however, high concentrations of CSE inhibited their proliferation. Low concentrations of CSE also markedly increased extracellular secretion of hydrogen peroxide, inhibited proliferation, induced Apoptosis and produced epithelial-mesenchymal transition (EMT) in cocultured A549 cells. This cigarette smoke-induced A549 cells EMT may become a new pathophysiological concept in the development of IPF. CSE possibly takes part in the development and progress of IPF by increasing oxidative stress.

Acta Diabetol. 2009 Nov 19;
Li B, Wang HS, Li GG, Zhao MJ, Zhao MH

The aim of this study was to evaluate the role of endoplasmic reticulum (ER) stress in diabetic retinopathy (DR) using in vitro and in vivo models. For the in vivo studies, diabetes was induced in rats, and retinal expression of glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), and vascular endothelial growth factor (VEGF) in groups of rats at 1, 3, and 6 months was assessed. For the in vitro studies, human retinal capillary endothelial cells (HRCECs) were cultured in the presence of varying glucose concentrations, and the expression of mRNA and protein for GRP78, ATF4, CHOP, and VEGF was assessed. The chosen glucose concentrations were reflective of those apparent in diabetic patients. Expression of VEGF and CHOP mRNA levels were significantly increased in diabetic rats compared to control rats at 1, 3, and 6 months (P < 0.05). In HRCECs cultured in the presence of high as well as variable glucose concentrations, CHOP expression and Apoptosis were significantly increased (P < 0.05). However, GRP78 and ATF4 expression levels were unchanged. Our findings suggest that early progression of DR may be mediated by ER stress, but probably does not involve changes in ATF4 or GRP78.

PLoS One. 2009; 4(11): e7774
Pohl NM, Tong C, Fang W, Bi X, Li T, Yang W

BACKGROUND: It has been shown that selenium-binding protein 1 (SBP1) is significantly downregulated in different human cancers. Its regulation and function have not yet been established. METHODOLOGY AND PRINCIPAL FINDINGS: We show that the SBP1 promoter is hypermethylated in colon cancer tissues and human colon cancer cells. Treatment with 5'-Aza-2'-deoxycytidine leads to demethylation of the SBP1 promoter and to an increase of SBP1 promoter activity, rescues SBP1 mRNA and protein expression in human colon cancer cells. Additionally, overexpression of SBP1 sensitizes colon cancer cells to H(2)O(2)-induced Apoptosis, inhibits cancer cell migration in vitro and inhibits tumor growth in nude mice. CONCLUSION AND SIGNIFICANCE: These data demonstrate that SBP1 has tumor suppressor functions that are inhibited in colorectal cancer through epigenetic silencing.

PLoS One. 2009; 4(11): e7889
Robert G, Ben Sahra I, Puissant A, Colosetti P, Belhacene N, Gounon P, Hofman P, Bost F, Cassuto JP, Auberger P

CML is an hematopoietic stem cell disease characterized by the t(9;22) (q34;q11) translocation encoding the oncoprotein p210BCR-ABL. The effect of acadesine (AICAR, 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside) a compound with known antileukemic effect on B cell chronic lymphoblastic leukemia (B-CLL) was investigated in different CML cell lines. Acadesine triggered loss of cell metabolism in K562, LAMA-84 and JURL-MK1 and was also effective in killing imatinib-resistant K562 cells and Ba/F3 cells carrying the T315I-BCR-ABL mutation. The anti-leukemic effect of acadesine did not involve Apoptosis but required rather induction of autophagic cell death. AMPK knock-down by Sh-RNA failed to prevent the effect of acadesine, indicating an AMPK-independent mechanism. The effect of acadesine was abrogated by GF109203X and Ro-32-0432, both inhibitor of classical and new PKCs and accordingly, acadesine triggered relocation and activation of several PKC isoforms in K562 cells. In addition, this compound exhibited a potent anti-leukemic effect in clonogenic assays of CML cells in methyl cellulose and in a xenograft model of K562 cells in nude mice. In conclusion, our work identifies an original and unexpected mechanism by which acadesine triggers autophagic cell death through PKC activation. Therefore, in addition to its promising effects in B-CLL, acadesine might also be beneficial for Imatinib-resistant CML patients.

Leukemia. 2009 Nov 19;
Belardo G, Piva R, Santoro MG

Nuclear factor-kappaB (NF-kappaB) is involved in multiple aspects of oncogenesis and controls cancer cell survival by promoting anti-apoptotic gene expression. The constitutive activation of NF-kappaB in several types of cancers, including hematological malignancies, has been implicated in the resistance to chemo- and radiation therapy. We have previously reported that cytokine- or virus-induced NF-kappaB activation is inhibited by chemical and physical inducers of the heat shock response (HSR). In this study we show that heat stress inhibits constitutive NF-kappaB DNA-binding activity in different types of B-cell malignancies, including multiple myeloma, activated B-cell-like (ABC) type of diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma presenting aberrant NF-kappaB regulation. Heat-induced NF-kappaB inhibition leads to rapid downregulation of the anti-apoptotic protein cellular inhibitor-of-Apoptosis protein 2 (cIAP-2), followed by activation of caspase-3 and cleavage of the caspase-3 substrate poly(adenosine diphosphate ribose)polymerase (PARP), causing massive Apoptosis under conditions that do not affect viability in cells not presenting NF-kappaB aberrations. NF-kappaB inhibition by the proteasome inhibitor bortezomib and by short-hairpin RNA (shRNA) interference results in increased sensitivity of HS-Sultan B-cell lymphoma to hyperthermic stress. Altogether, the results indicate that aggressive B-cell malignancies presenting constitutive NF-kappaB activity are sensitive to heat-induced Apoptosis, and suggest that aberrant NF-kappaB regulation may be a marker of heat stress sensitivity in cancer cells.Leukemia advance online publication, 19 November 2009; doi:10.1038/leu.2009.227.

Leukemia. 2009 Nov 19;
Puissant A, Colosetti P, Robert G, Cassuto JP, Raynaud S, Auberger P

Imatinib is the leading compound to treat patients with chronic myelogenous leukemia (CML) but the exact mechanism of its anti-leukemic effect is incompletely elucidated. Through inhibition of BCR-ABL, Imatinib blocks several downstream pathways and induces Apoptosis of BCR-ABL positive cells. In this study, we analyzed further the mode of action of Imatinib in different appropriate cellular models of CML either sensitive or resistant to Imatinib and in CD34+ cells from CML patients. Pharmacological or short hairpin RNA-mediated inhibition of BCR-ABL triggers lysosomal membrane permeabilization (LMP) that culminates in activation and redistribution of Cathepsin B (CB) into the cytoplasm of CML cells, in which it triggers directly BCR-ABL degradation. Pharmacological inhibition of CB by CA-074Me or small interfering RNA-mediated knock-down of CB partly protects K562 cells from Imatinib-induced cell death and CB overexpression sensitizes these cells to Imatinib killing. Strikingly, Imatinib-triggered LMP, CB activation and BCR-ABL cleavage in CD34+ cells from CML patients and inhibition of CB confers protection against cell death in clonogenic assays of CD34+ primary cells from CML patients. Hence, we describe an original pathway by which Imatinib participates to the elimination of CML cells through LMP and CB-mediated specific degradation of BCR-ABL.Leukemia advance online publication, 19 November 2009; doi:10.1038/leu.2009.233.

Shock. 2009 Nov 17;
Di Paola R, Melani A, Esposito E, Mazzon E, Paterniti I, Bramanti P, Pedata F, Cuzzocrea S

In the present study, we tested the efficacy of treatment with the selective adenosine A2A receptor agonist 2-[ p-(2-carboxyethyl)phenylethylamino]-50-ethylcarboxamidoadenosine (CGS 21680) on ischemia and reperfusion injury of the multivisceral organs.Ischemia and reperfusion injury was induced in mice by clamping both the superior mesenteric artery and the celiac artery for 30 min, followed thereafter by reperfusion. Sixty minutes after reperfusion, animals were sacrificed for histological examination and biochemical studies. Injured vehicle-treated mice developed a significant increase of ileum TNF-alphalevels, myeloperoxidase activity and marked histological injury and Apoptosis. Ischemia and reperfusion injury of the multivisceral organs was also associated with a significant mortality. Reperfused ileum sections from injured vehicle-treated mice showed positive staining for P-selectin and ICAM-1.The intensity and degree of P-selectin and ICAM-1 were markedly reduced in tissue section from injured- CGS 21680 treated mice. Ischemia and reperfusion injured mice which have been treated with CGS 21680 showed also a significant reduction of neutrophil infiltration into the intestine, a reduction of Apoptosis, an improved histological status of the intestine and survival.Taken together, our results clearly demonstrate that selective activation of adenosine A2A receptors play an important role in the regulation of ischemia and reperfusion injury and put forward the hypothesis that selective activation of adenosine A2A receptors may represent a novel and possible strategy.

Autophagy. 2010 Jan 27; 6(1):
Yan J, Yang H, Wang G, Sun L, Zhou Y, Guo Y, Xi Z, Jiang X

Troglitazone is a synthetic ligand of peroxisome proliferators activated receptor-gamma (PPARgamma) and induces Apoptosis in a variety of malignant cells. However, the underlying mechanism of its regulatory role in macroautophagy (hereafter autophagy) remains largely unknown. Using fluorescence and electron microscopy, we observed that autophagosomes could be induced and identified upon troglitazone challenge in both primary and epidermal growth factor receptor (EGFR)-expressed porcine aortic endothelial (PAE) cells. We report here that troglitazone augments AMP-activated protein kinase-alpha (AMPKalpha) phosphorylation, reduces p70S6 kinase phosphorylation and stimulates autophagy that is independent of EGFR expression and transactivation. Troglitazone stimulus reduced neither lysosomal staining nor GFP-LC3 dots of HeLa cells, when the cells pretreated with AG1478, a specific EGFR kinase inhibitor. Furthermore, AG1478 additively enhanced the troglitazone-induced degradation of sequestosome 1 (SQSTM1/p62), which is a selective substrate of autophagy. Inhibition of AMPKalpha activity either by compound C or by RNA interference markedly reduced the accumulation of microtubule-associated protein 1 light chain 3-II (LC3-II ), a good indicator of autophagy; whereas blockage of PPARgamma activity by the irreversible antagonist GW9662 or by overexpressing dominate-negative PPARgamma did not affect LC3-II accumulation and AMPK phosphorylation. Taken together, we demonstrate that autophagy promoted via troglitazone is correlated with AMPKalpha activation and independent of PPARgamma activation and EGFR transactivation.

Cancer Biol Ther. 2010 Jan 9; 9(1):
Shen J, Li G, Liu Q, He Q, Gu J, Shi Y, Lou H

Cancer cell migration is a leading cause of tumor recurrence and treatment failure. Previously, we reported that marchantin C exhibited promising antitumor activity by inducing microtubule depolymerization and Apoptosis. In the present study, we investigated the effect of marchantin C on inhibition of migration in T98G and U87 cells. The scratch-induced migration, Boyden chamber and cell invasion assays were applied to determine that the migrating capacity and invasiveness of these glioma cell lines were inhibited when exposed to marchantin C at a low concentration. There are no obvious signs of Apoptosis with this dose. Western blot analyses confirmed that MMP-2, a key role in cancer cell migration, was reduced after incubation with marchantin C in both glioma cell lines. In addition, signaling pathway investigations demonstrated that ERK/MAPK might be involved in MMP-2 downregulation, rather than the AKT/PI3K or JAK/STAT3 pathways. Moreover, marchantin C potently suppressed angiogenesis activity in vivo by CAM assay. This is the first study to demonstrate that marchantin C can inhibit glioma cell migration and invasiveness.

Cancer Biol Ther. 2009 Dec 19; 8(24):
No M, Choi EJ, Kim IA

Several studies have indicated the potential value of targeting HER-2 signaling to enhance the anti-tumor activity of ionizing radiation. However, therapeutic resistance resulting from several factors, including activation of the downstream pathway, represents a major obstacle to treatment. Here, we investigated whether inhibitors targeting downstream of HER-2 signaling would radiosensitize SKBR3 breast cancer cells that exhibit overamplification of HER2. Selective inhibition of MEK-ERK signaling using pharmacologic inhibitors (PD98059, UO126) did not increase the radiosensitivity of SKBR3 cells. Selective inhibition of the PI3K-AKT-mTOR pathway using pharmacologic inhibitors (LY294002, AKT inhibitor VIII, Rapamycin) significantly attenuated expression of p-AKT and p-70S6K, respectively and radiosensitized SKBR3 cells. MCF-7 cells those did not overexpress HER-2, showed less radiosensitization compared to SKBR3 cells by inhibition of this pathway. Pre-treatment with these inhibitors also caused significant abrogation of typical G(2) arrest following ionizing radiation and induced marked prolongation of gammaH2AX foci indicating impairment of DNA damage repair. A dual inhibitor of Class I PI3K and mTOR, PI103 effectively radiosensitized SKBR3 cells and showed significant prolongation of gammaH2AX foci. Inhibition of PI3K-AKT signaling was associated with downregulation of DNA-PKs, respectively. While Apoptosis was the major mode of cell death when the cells were pretreated with LY294002 or AKT inhibitor VIII, the cells were pretreated by rapamycin or PI103 showed mixed mode of cell death including autophagy. Our results suggest possible mechanisms to counteract the HER-2 prosurvival signaling implicated in radioresistance, and offer an alternative strategy to overcome resistance to HER-2 inhibitors combined with radiation.

Cancer Biol Ther. 2010 Jan 17; 9(1):
do Carmo A, Patricio I, Cruz MT, Carvalheiro H, Oliveira CR, Lopes MC

Glioblastoma (GBM) is the most aggressive and malignant brain tumor. Recent studies indicated that glioma samples are characterized by increased expression of CXCR4, the CXCL12/SDF-1 chemokine receptor. To better understand the role of CXCR4 in GBM biology we performed an integrated study where we simultaneously evaluate the contribution of the CXCR4/CXCL12 signaling pathway to the proliferation, survival and motility of a human GBM cell line. Our results indicated that CXCR4/CXCL12 axis induced an increase in cell proliferation and in cell motility. The blockage of CXCR4 induced a significant increase of Apoptosis. Together, our results indicated that CXCR4/CXCL12 signalling pathway may contribute to GBM development and emphasize the therapeutic potential of this pathway in patients with GBM.

Autophagy. 2010 Jan 29; 6(1):
Alonso-Curbelo D, Soengas MS

Patients with metastatic melanoma have a poor prognosis, primarily due to a generalized inefficacy of current anticancer treatments. Therefore, the identification of novel death inducers with good bioavailability and safety profiles is a main priority in this disease. Here we summarize recent work from our group uncovering an unexpected ability of the dsRNA mimic polyinosine-polycytidylic acid (pIC) to engage the endo/lysosomal machinery of melanoma cells and induce their self degradation by autophagy and Apoptosis, without noticeable secondary effects in vivo. However the antimelanoma activity of pIC strictly required conjugation with carriers (e.g., polyethyleneimine, PEI) for cytosolic delivery. Combining transcriptome analyses with RNA interference, we found RNA helicase MDA-5 as a main driver of the pIC-PEI complex. MDA-5 in turn, favored NOXA-dependent activation of apoptotic caspases. These results demonstrate new therapeutically tractable links between autophagy and Apoptosis that can be coordinately engaged in tumor cells by dsRNA mimics.