scholarly journals Mechanisms of stearoyl CoA desaturase inhibitor sensitivity and acquired resistance in cancer

2021 ◽  
Vol 7 (7) ◽  
pp. eabd7459
Author(s):  
Nicole Oatman ◽  
Nupur Dasgupta ◽  
Priyanka Arora ◽  
Kwangmin Choi ◽  
Mruniya V. Gawali ◽  
...  
Keyword(s):  
Cell Lines ◽  
Acquired Resistance ◽  
Normal Brain ◽  
Unexpected Finding ◽  
Epigenetic Alterations ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Stearoyl Coa Desaturase ◽  
Murine Osteosarcoma ◽  
Viral Oncogene Homolog

The lipogenic enzyme stearoyl CoA desaturase (SCD) plays a key role in tumor lipid metabolism and membrane architecture. SCD is often up-regulated and a therapeutic target in cancer. Here, we report the unexpected finding that median expression of SCD is low in glioblastoma relative to normal brain due to hypermethylation and unintentional monoallelic co-deletion with phosphatase and tensin homolog (PTEN) in a subset of patients. Cell lines from this subset expressed undetectable SCD, yet retained residual SCD enzymatic activity. Unexpectedly, these lines evolved to survive independent of SCD through unknown mechanisms. Cell lines that escaped such genetic and epigenetic alterations expressed higher levels of SCD and were highly dependent on SCD for survival. Last, we identify that SCD-dependent lines acquire resistance through a previously unknown FBJ murine osteosarcoma viral oncogene homolog B (FOSB)–mediated mechanism. Accordingly, FOSB inhibition blunted acquired resistance and extended survival of tumor-bearing mice treated with SCD inhibitor.

scholarly journals An Immunohistochemical Study of the PTEN/AKT Pathway Involvement in Canine and Feline Mammary Tumors

Animals ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 365
Author(s):  
Pietro Asproni ◽  
Francesca Millanta ◽  
Lorenzo Ressel ◽  
Fabio Podestà ◽  
Francesca Parisi ◽  
...  
Keyword(s):  
Immunohistochemical Study ◽  
Lymphatic Invasion ◽  
Pten Expression ◽  
Akt Pathway ◽  
Phosphatase And Tensin Homolog ◽  
Mammary Carcinomas ◽  
Tensin Homolog ◽  
Aggressive Tumors ◽  
Aggressive Subtype ◽  
Viral Oncogene Homolog

Phosphatase and tensin homolog deleted on chromosome10 (PTEN), phospho-v-Akt murine thymoma viral oncogene homolog (AKT), and the Rapamycin-Insensitive Companion of mTOR (Rictor) expression was investigated by immunohistochemistry in 10 canine mammary adenomas (CMAs), 40 canine mammary carcinomas (CMCs), and 30 feline mammary carcinomas (FMCs). All the CMAs, 25 of 40 CMCs (63%) and 7 of 30 FMCs (23%), were PTEN-positive. In dogs, no CMAs and 15 of 25 CMCs (37%) expressed phospho-AKT (p-AKT), while 24 of 30 FMCs (82%) were p-AKT-positive. One of 10 CMAs (10%), 24 of 40 CMCs (60%) and 20 of 30 FMCs (67%) were Rictor-positive. In the dog, PTEN expression correlated with less aggressive tumors, absence of lymphatic invasion, and longer survival. P-AKT expression correlated with more aggressive subtype, lymphatic invasion, and poorer survival and Rictor expression with lymphatic invasion. In cats, PTEN correlated with less aggressive carcinomas, absence of lymphatic invasion, and better survival. P-AKT and Rictor expression correlated with poorer survival. PTEN expression was inversely correlated with p-AKT and Rictor in both species, while p-AKT positively correlated with Rictor expression. A strong PTEN/AKT pathway involvement in behavior worsening of CMT and FMTs is demonstrated, providing a rationale for further studies of this pathway in veterinary oncology.

scholarly journals The Major Target of the Endogenously Generated Reactive Oxygen Species in Response to Insulin Stimulation Is Phosphatase and Tensin Homolog and Not Phosphoinositide-3 Kinase (PI-3 Kinase) in the PI-3 Kinase/Akt Pathway

2005 ◽  
Vol 16 (1) ◽  
pp. 348-357 ◽  
Author(s):  
Ji Hae Seo ◽  
Younghee Ahn ◽  
Seung-Rock Lee ◽  
Chang Yeol Yeo ◽  
Kyu Chung Hur
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Lines ◽  
Membrane Fraction ◽  
Akt Pathway ◽  
Oxygen Species ◽  
Insulin Stimulation ◽  
Phosphatase And Tensin Homolog ◽  
Downstream Signaling ◽  
Tensin Homolog ◽  
Phosphoinositide 3 Kinase

Phosphoinositide-3 kinase (PI-3 kinase) and its downstream signaling molecules PDK-1 and Akt were analyzed in SK-N-SH and SK-N-BE(2) human neuroblastoma cell lines. When cells were stimulated with insulin, PI-3 kinase was activated in both cell lines, whereas the translocation of PDK-1 to the membrane fraction and phosphorylated Akt were observed only in SK-N-SH cells. Analyses of the insulin-mediated reactive oxygen species (ROS) generation and Phosphatase and Tensin homolog (PTEN) oxidation indicate that PTEN oxidation occurred in SK-N-SH cells, which can produce ROS, but not in SK-N-BE(2) cells, which cannot increase ROS in response to insulin stimulation. When SK-N-SH cells were pretreated with the NADPH oxidase inhibitor diphenyleneiodonium chloride before insulin stimulation, insulin-mediated translocation of PDK-1 to the membrane fraction and phosphorylation of Akt were remarkably reduced, whereas PI-3 kinase activity was not changed significantly. These results indicate that not only PI-3 kinase activation but also inhibition of PTEN by ROS is needed to increase cellular level of phosphatidylinositol 3,4,5-trisphosphate for recruiting downstream signaling molecules such as PDK-1 and Akt in insulin-mediated signaling. Moreover, the ROS generated by insulin stimulation mainly contributes to the inactivation of PTEN and not to the activation of PI-3 kinase in the PI-3 kinase/Akt pathway.

EXTH-50. THE COMPLEXITIES OF FATTY ACID DESATURATION IN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi174-vi174
Author(s):  
Nicole Oatman ◽  
Biplab Dasgupta
Keyword(s):  
Fatty Acid ◽  
Cell Lines ◽  
Acyl Chain ◽  
Acquired Resistance ◽  
Enzymatic Reaction ◽  
Monounsaturated Fatty Acids ◽  
Fatty Acid Desaturation ◽  
Normal Brain ◽  
Drug Induced ◽  
Essential Components

Abstract Fatty acid desaturation is an enzymatic reaction in which a double bond is introduced into an acyl chain. Monounsaturated fatty acids (MUFA) are essential components of membrane. The most abundant MUFA-synthesizing enzyme is the delta 9 desaturate called Stearoyl Co-A Desaturase (SCD and SCD5 in humans, and SCD1-4 in mice). SCD desaturates Stearoyl-CoA (C18) and palmitoyl-CoA (C16) to oleoyl-CoA (C18:1) and palmitoyl-CoA (C16:1), respectively. SCD is often upregulated and a therapeutic target in cancer. We made an unexpected discovery that that median expression of SCD is low in glioblastoma relative to normal brain due to hypermethylation and monoallelic co-deletion with the tumor suppressor PTEN in a subset of patients. Cell lines from this subset, expressed nearly undetectable SCD yet they retained residual SCD enzymatic activity. Surprisingly, these lines evolved to survive independent of SCD through unknown mechanisms. On the other hand, cell lines that escaped such genetic and epigenetic alterations expressed higher levels of SCD and were highly dependent on SCD for survival. Finally, we identify that SCD-dependent lines acquire resistance through a previously unknown mechanism that involved drug-induced target (SCD) upregulation by the transcription factor FOSB. Accordingly, FOSB inhibition blunted acquired resistance and extended survival of tumor bearing mice treated with SCD inhibitor. Our findings reveal an intriguing feature of the cancer genome that may be used to stratify PTEN deleted cancer patients for SCD inhibitor therapy. A recent study showed that some cancer cells can use another MUFA-synthesizing enzyme FADS2 to bypass the SCD reaction. However, our data shows that the SCD inhibitor- resistant GBM lines are also FADS2-independent. Our targeted and untargeted metabolomics studies revealed unexpected findings that cannot be explained by conventional wisdom, and may lead to identification of novel lipogenic targets in GBM.

scholarly journals Multiple signaling pathways induced by hexavalent, monospecific, anti-CD20 and hexavalent, bispecific, anti-CD20/CD22 humanized antibodies correlate with enhanced toxicity to B-cell lymphomas and leukemias

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3258-3267 ◽  
Author(s):  
Pankaj Gupta ◽  
David M. Goldenberg ◽  
Edmund A. Rossi ◽  
Chien-Hsing Chang
Keyword(s):  
Cell Lines ◽  
Chronic Lymphocytic Leukemia Patient ◽  
In Vitro Cytotoxicity ◽  
Lymphocytic Leukemia ◽  
Lymphoma Cell ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Depth Analysis ◽  
Anti Cd20

Abstract We have generated hexavalent antibodies (HexAbs) comprising 6 Fabs tethered to one Fc of human IgG1. Three such constructs, 20-20, a monospecific HexAb comprising 6 Fabs of veltuzumab (humanized anti-CD20 immunoglobulin G1κ [IgG1κ]), 20-22, a bispecific HexAb comprising veltuzumab and 4 Fabs of epratuzumab (humanized anti-CD22 IgG1κ), and 22-20, a bispecific HexAb comprising epratuzumab and 4 Fabs of veltuzumab, were previously shown to inhibit pro-liferation of several lymphoma cell lines at nanomolar concentrations in the absence of a crosslinking antibody. We now report an in-depth analysis of the apoptotic and survival signals induced by the 3 HexAbs in Burkitt lymphomas and provide in vitro cytotoxicity data for additional lymphoma cell lines and also chronic lymphocytic leukemia patient specimens. Among the key findings are the significant increase in the levels of phosphorylated p38 and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) by all 3 HexAbs and the notable differences in the signaling events triggered by the HexAbs from those incurred by crosslinking veltuzumab or rituximab with a secondary antibody. Thus, the greatly enhanced direct toxicity of these HexAbs correlates with their ability to alter the basal expression of various intracellular proteins involved in regulating cell growth, survival, and apoptosis, with the net outcome leading to cell death.

scholarly journals LPTO-06. A NOVEL BRAIN-PERMEANT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF BREAST CANCER LEPTOMENINGEAL METASTASIS

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i7-i7
Author(s):  
Jiaojiao Deng ◽  
Sophia Chernikova ◽  
Wolf-Nicolas Fischer ◽  
Kerry Koller ◽  
Bernd Jandeleit ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Tumors ◽  
Cell Lines ◽  
Chemotherapeutic Agent ◽  
Leptomeningeal Metastasis ◽  
Breast Cancer Cell Lines ◽  
Normal Brain ◽  
Breast Cancers

Abstract Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). The compound is active in suppressing the growth of GBM tumor cell lines implanted into the brain. Radiolabel distribution studies have shown significant tumor accumulation in intracranial brain tumors while sparing the adjacent normal brain tissue. Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106 photons/sec, mice were dosed i.p. twice a week with either 4 or 8 mg/kg for nine weeks. Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.43

scholarly journals High Throughput Screen Identifies the DNMT1 (DNA Methyltransferase-1) Inhibitor, 5-Azacytidine, as a Potent Inducer of PTEN (Phosphatase and Tensin Homolog)

2020 ◽  
Vol 40 (8) ◽  
pp. 1854-1869
Author(s):  
Keith A. Strand ◽  
Sizhao Lu ◽  
Marie F. Mutryn ◽  
Linfeng Li ◽  
Qiong Zhou ◽  
...  
Keyword(s):  
Protein Expression ◽  
High Throughput ◽  
Knockout Mice ◽  
Vascular Remodeling ◽  
Dna Methyltransferase ◽  
Dna Methyltransferase 1 ◽  
Protective Effects ◽  
High Throughput Screen ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog

Objective: Our recent work demonstrates that PTEN (phosphatase and tensin homolog) is an important regulator of smooth muscle cell (SMC) phenotype. SMC-specific PTEN deletion promotes spontaneous vascular remodeling and PTEN loss correlates with increased atherosclerotic lesion severity in human coronary arteries. In mice, PTEN overexpression reduces plaque area and preserves SMC contractile protein expression in atherosclerosis and blunts Ang II (angiotensin II)-induced pathological vascular remodeling, suggesting that pharmacological PTEN upregulation could be a novel therapeutic approach to treat vascular disease. Approach and Results: To identify novel PTEN activators, we conducted a high-throughput screen using a fluorescence based PTEN promoter-reporter assay. After screening ≈3400 compounds, 11 hit compounds were chosen based on level of activity and mechanism of action. Following in vitro confirmation, we focused on 5-azacytidine, a DNMT1 (DNA methyltransferase-1) inhibitor, for further analysis. In addition to PTEN upregulation, 5-azacytidine treatment increased expression of genes associated with a differentiated SMC phenotype. 5-Azacytidine treatment also maintained contractile gene expression and reduced inflammatory cytokine expression after PDGF (platelet-derived growth factor) stimulation, suggesting 5-azacytidine blocks PDGF-induced SMC de-differentiation. However, these protective effects were lost in PTEN-deficient SMCs. These findings were confirmed in vivo using carotid ligation in SMC-specific PTEN knockout mice treated with 5-azacytidine. In wild type controls, 5-azacytidine reduced neointimal formation and inflammation while maintaining contractile protein expression. In contrast, 5-azacytidine was ineffective in PTEN knockout mice, indicating that the protective effects of 5-azacytidine are mediated through SMC PTEN upregulation. Conclusions: Our data indicates 5-azacytidine upregulates PTEN expression in SMCs, promoting maintenance of SMC differentiation and reducing pathological vascular remodeling in a PTEN-dependent manner.

miR-139-5p promotes neovascularization in diabetic retinopathy by regulating the phosphatase and tensin homolog

2021 ◽  
Vol 44 (2) ◽  
pp. 205-218
Author(s):  
Zhongwei Zhang ◽  
Caiping Song ◽  
Tao Wang ◽  
Lei Sun ◽  
Ling Qin ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog

scholarly journals The Mitochondrial Kinase PINK1 in Diabetic Kidney Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 1525
Author(s):  
Chunling Huang ◽  
Ji Bian ◽  
Qinghua Cao ◽  
Xin-Ming Chen ◽  
Carol A. Pollock
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Kidney Diseases ◽  
Mitochondrial Protein ◽  
Physiological Role ◽  
Close Link ◽  
Promising Alternative ◽  
Diabetic Kidney ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog

Mitochondria are critical organelles that play a key role in cellular metabolism, survival, and homeostasis. Mitochondrial dysfunction has been implicated in the pathogenesis of diabetic kidney disease. The function of mitochondria is critically regulated by several mitochondrial protein kinases, including the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1). The focus of PINK1 research has been centered on neuronal diseases. Recent studies have revealed a close link between PINK1 and many other diseases including kidney diseases. This review will provide a concise summary of PINK1 and its regulation of mitochondrial function in health and disease. The physiological role of PINK1 in the major cells involved in diabetic kidney disease including proximal tubular cells and podocytes will also be summarized. Collectively, these studies suggested that targeting PINK1 may offer a promising alternative for the treatment of diabetic kidney disease.

Sign in / Sign up

Export Citation Format

Share Document