ROLE OF MONOUNSATURATED FATTY ACID SYNTHESIS IN HUMAN CELL PROLIFERATION, SURVIVAL, DIFFERENTIATION, AND TRANSFORMATION TO CANCER

• Sponsoring Institution: National Institute of Food and Agriculture
• Project Status: COMPLETE
• Funding Source: HATCH
• Reporting Frequency: Annual
• Accession No.: 0216489
• Project Start Date: Oct 1, 2008
• Project End Date: Sep 30, 2013
• Program Code: [(N/A)]- (N/A)

Recipient Organization
RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY
3 RUTGERS PLZA
NEW BRUNSWICK,NJ 08901-8559

Performing Department
Nutritional Sciences

Non Technical Summary
Cancer is one of the leading causes of mortality in the US and worldwide. One out of three people in the US develop some form of cancer during their lifetime and approximately one fourth succumb to the disease [American Cancer Society, 2006]. In New Jersey, cancer is the number one cause of death among adults ages 35 to 64, with lung and breast cancer at the top of the list of the most frequent and lethal cancer types. Despite certain progress in early detection and better treatment, the survival rate of both cancers is still disappointingly low. Hence, the need for better cancer treatment is clear. In the search for novel therapies, attention has been focused on new molecular targets, among which lipid metabolism has emerged as a new potential site for intervention. In this regard, we have recently found that Stearoyl-CoA desaturase 1 (SCD1), the main human SCD isoform that converts saturated fatty acids (SFA) into monounsaturated fatty acids (MUFA), is a global regulator of lipid synthesis in human lung cancer cells and that the reduction in SCD1 gene expression attenuates or abolishes several features of malignancy. Preliminary data indicates that SCD1 activity controls the proliferation rate of both lung and breast cancer cells. Our research will reveal the molecular aspects of the functional connection between the regulation of cellular metabolism by SCD1 and the mechanisms of cancer. Moreover, our work is expected to provide confirmatory evidence that, by reducing SCD1 activity in cancer cells, the essential structural, energetic, and signaling functions carried out by endogenous MUFA will be impaired, leading to a reversion of the malignant phenotype. From a clinical perspective, targeting SCD1 in human cancer cells may as well offer a molecular rationale for new therapeutic interventions based on nutritional and pharmacological interventions. Finally, if SCD1 regulates the activity of signaling networks activated in cancer, the pharmacological inhibition of SCD1 could promote sensitization of cancer cells to anticancer drugs affecting receptor-mediated signaling.

Animal Health Component

(N/A)

Research Effort Categories

Basic

(N/A)

Applied

(N/A)

Developmental

(N/A)

Classification

Knowledge Area (KA)	Subject of Investigation (SOI)	Field of Science (FOS)	Percent
702	3840	1000	10%
702	3840	1010	10%
702	3840	1030	10%
702	3840	1040	10%
702	7010	1000	10%
702	7010	1010	20%
702	7010	1030	20%
702	7010	1040	10%

Knowledge Area
702 - Requirements and Function of Nutrients and Other Food Components;

Subject Of Investigation
3840 - Laboratory animals; 7010 - Biological Cell Systems;

Field Of Science
1040 - Molecular biology; 1030 - Cellular biology; 1010 - Nutrition and metabolism; 1000 - Biochemistry and biophysics;

Keywords

lipid metabolism

fatty acids

nutrition

cell cycle

cell death

human cancer

Goals / Objectives
We and others have reported a positive correlation between high levels of MUFA and several types of malignancies. Importantly, alterations in the expression and activity of the main SCD isoform, SCD1, have been associated with cancer. Our laboratory was the first to demonstrate that malignant transformation in human cells was strongly correlated with a parallel activation of SCD1 expression and fatty acid synthesis, resulting in increased content of MUFA in membrane lipids and in a modification of the physical-chemical properties of cellular membranes. Further, we demonstrated that a blockade of SCD1 gene expression in human lung cancer cell lines resulted in dramatic changes in lipid metabolism and, consequently, in cancer cell phenotype. In a recent study designed to identify new cancer targets, a siRNA library against 3,700 genes was screened in several cancer cells in search for suitable targets for inducing cytotoxicity and cell death. Remarkably, SCD1 was one of the three main targets identified in the screening, confirming our observations that SCD1 activity may be essential for cancer cell proliferation and survival. Nevertheless, the molecular mechanisms by which SCD1 participates in the regulation of carcinogenesis are still largely unknown, leading us to explore the role of SCD1 in cancer, one of the most common and lethal diseases for which therapeutic options remain limited. Using cultured lung cancer cells and mouse tumor models, we will elucidate the role of SCD1 in 1) the regulation of critical steps in glucose-derived lipid synthesis and lipid oxidation in human cancer cells; 2) the regulation of signaling networks that the control of metabolism in cancer cell, paying special attention to two major regulators of lipid anabolism and catabolism: phosphatidylinositol-3 kinase (PI3K)-Akt pathway (or Akt pathway), and AMP-activated protein kinase (AMPK) pathway; and 3) tumor formation and growth in mice models of lung cancer.

Project Methods
Our overall hypothesis is that SCD1, via its key role in lipid metabolism and specific effects on signaling pathways, modulates the events of cell cycle, differentiation and senescence in normal cells and the malignant biological and biochemical phenotype of cancer cells. SCD1 may be a potential target for pharmacological intervention in several diseases including aging, diabetes and cancer. We will assess the following research aims: Aim 1. To elucidate the mechanisms by which SCD1 modulates cell growth, apoptosis, differentiation and senescence in human cells. We will determine if the reduction of SCD1 levels will decrease cell growth by affecting the progression through specific phases of cell cycle in normal cells. We speculate that low expression of SCD1 in normal cells will induce cell arrest or senescence. Also, we will investigate if low SCD1 activity will block the progression of cell cycle in cancer cells, thereby inducing cell suicide by apoptosis. Finally, we will assess whether differentiation of normal and cancer cells is determined by the rate of SCD1 activity. Aim 2. To investigate the mechanisms by which SCD1 regulates the Akt signaling pathway in cancer cells. We will determine if SCD1, by regulating the balance of MUFA/SFA in plasma membrane, modify the activity of components of the Akt signaling pathway that either reside in or interact with the cell membrane, thereby modulating cell lipid metabolism and, consequently, the biological phenotype of cancer cells. Aim 3. To elucidate the role of SCD1 in the regulation of lipid anabolism and catabolism in cancer cells. We will investigate if inhibition of SCD1 expression will decrease the de novo synthesis of lipids by a coordinated downregulation of rate-limiting enzymes of fatty acid synthesis. We will also determine whether SREBP-1, a central regulator of lipogenesis, is implicated in the control of lipid synthesis by SCD1 in cancer cells. In addition, we will determine if the limited production of lipids in SCD1-depleted cells is accompanied by an increase in lipid oxidation induced by the activation of AMPK, a master controller of cell energy homeostasis. Aim 4. To characterize the mechanisms by which SCD1 regulates tumor formation and invasion in vivo. We will characterize the participation of SCD1 in tumor formation and progression to metastasis by investigating the effects of SCD1-ablation on tumor cell biology and in the process of carcinogenesis in mice models. In addition, the potential role of dietary SFA as enhancers of the antitumoral effect of SCD1 inhibition will be addressed.

Progress 10/01/08 to 09/30/13

Outputs
OUTPUTS: Project director has left the university. PARTICIPANTS: Not relevant to this project. TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Not relevant to this project.

Impacts
Project director has left the University.

Publications

• No publications reported this period

Progress 01/01/11 to 12/31/11

Outputs
OUTPUTS: Experiments: 1) Experimental model: Human cancer cells deficient in lipogenic enzymes were assessed through specific pharmacological inhibition. Expression and activity of this enzyme was assessed. 2) Studies of signal transduction activity. Analysis of cancer cell proliferation. 3) Determination of plasma membrane mobility and functionality. A) Undergraduate Students: Nana Sasu, Rutgers University Department of Nutritional Sciences. Ksenia Rogalo, Rutgers University Department of Nutritional Sciences. B) Graduate Students: Daniel Hess, Rutgers University, Nutritional Sciences program. Mary Nashed, Rutgers University, Nutritional Sciences program. Jung Kim, Rutgers University, Food Science program. Teaching: Nutrition: A Biochemical and Physiological Basis (16:709:552) Advanced Nutrition II:Energy and Micronutrient Metabolism (11:709:401) Nutrition Seminar (16:709:601 Events: A) Lectures: November 2011, Novartis Laboratories, East Hanover, NJ. Title: Metabolic enzymes: new players, novel pharmacological targets. PARTICIPANTS: Undergraduate Students: Nana Sasu,Ksenia Rogalo. Graduate Students: Daniel Hess, Mary Nashed, Jung Kim. TARGET AUDIENCES: Target audiences: Academic: areas of nutrition, biology, physiology and biochemistry. Cancer biology and therapeutics Industry: nutrition and foods, biotechnology, pharmaceutics, drug development. PROJECT MODIFICATIONS: Not relevant to this project.

Impacts
StearoylCoA Desaturase-1 (SCD1), the main enzyme that converts saturated into monounsaturated fatty acids, is a key factor in the mechanisms of cancer cell proliferation, survival and tumorigenesis. Evidence indicates that SCD-1 activity regulates these events in part by targeting the phosphatidylinositol-3 phosphate kinase (PI3K)/Akt pathway, but the molecular mechanisms remains unknown. We now show that in H460 lung cancer cells, the suppression of SCD activity with CVT-11127, a specific small molecule SCD inhibitor, impairs the ligand-induced phosphorylation of epidermal growth factor (EGF) receptor, causing the inactivation of its downstream targets Akt, ERK and mTOR. Importantly, the mitogenic response to epidermal growth factor (EGF) was markedly defective in SCD-depleted cancer cells. The inactivation of EGF receptor (EGFR) by SCD inhibition may be caused by perturbations in the lipid microenvironment surrounding the receptor, since we detected significant alterations in the lateral mobility of plasma lipid microdomains. Finally, incubation of lung cancer cells with gefitinib, an EGFR inhibitor employed in cancer treatment, potentiated the anti-growth effect of the SCD blocker. Our data indicate that SCD activity may control cancer cell metabolism, proliferation and survival, at least in part, by modulating the EGFRAkt/ERK signaling platforms. Our studies also suggest a value for SCD inhibitors as novel pharmacological agents in lung cancer, one of the most common and lethal forms of cancer for which therapeutic options remain very limited.

Publications

• Hess D., Igal R. A. Genistein downregulates de novo lipid synthesis and cell proliferation rate in human lung cancer cells. (2011) Experimental Biology and Medicine 236:707-13.
• Igal, R. A.. Roles of StearoylCoA desaturase-1 in cancer cell proliferation, programmed cell death and tumorigenesis. (2011) Cancers 2:2462-2477.

Progress 01/01/10 to 12/31/10

Outputs
OUTPUTS: Experiments: 1) Experimental model: Human cancer cells deficient in lipogenic enzymes were assessed through specific pharmacological inhibition. Expression and activity of this enzyme was assessed. 2) Studies of lipid metabolism: determination of lipid content and composition, de novo synthesis of lipids. Analysis of cell cycle mechanisms: determination of cell cycle phases and critical regulating proteins. A) Undergraduate Students: Nana Sasu, Rutgers University Department of Nutritional Sciences. Ksenia Rogalo, Rutgers University Department of Nutritional Sciences. Hayley Hoffman, University of Rochester B) Graduate Students: Daniel Hess, Rutgers University, Nutritional Sciences program. Mary Nashed, Rutgers University, Nutritional Sciences program. Jung Kim, Rutgers University, Food Science program. Teaching: Nutrition: A Biochemical and Physiological Basis (16:709:552) Advanced Nutrition II:Energy and Micronutrient Metabolism (11:709:401) Nutrition Seminar (16:709:601 Events: A) Lectures: 1. Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University. October, 8th, 2009. Role of StearoylCoA desaturase-1 in cancer. 2. Endocrinology and Animal Biosciences, Rutgers University, Title: Role of Lipid Metabolism in cell proliferation, survival and transformation to cancer. February 20th, 2009 B): Communications in scientific meetings: 1.Igal, R. A., Seminar, Department of Nutritional Sciences, Rutgers University. October 6th, 2010. StearoylCoA Desaturase-1: a key modulator of metabolic and signaling pathways in cancer. 2.J. Y. Kim, D. Hess, R. A. Igal. Regulation of StearoylCoA desaturases-1 and -5 in human cells: role of exogenous fatty acids and growth factors. Pioneers in Endocrinology Workshop: Nutrition and Metabolic Health, Rutgers University, NJ. September 22nd, 2010. 3.M. Nashed, D. Hess, R. A. Igal. StearoylCoA desaturase activity modulates the activation of EGF receptors in lung cancer cells. Pioneers in Endocrinology Workshop: Nutrition and Metabolic Health, Rutgers University, NJ. September 22nd, 2010. 4. D. Hess, R. A. Igal. Genistein downregulates de novo lipid synthesis and cell proliferation rate in human lung cancer cells. Pioneers in Endocrinology Workshop: Nutrition and Metabolic Health, Rutgers University, NJ. September 22nd, 2010. 5. M. Nashed, N. Scaglia, D. Hess, J. W. Chisholm, R. A. Igal. StearoylCoA desaturase activity modulates the activation of EGF receptors in lung cancer cells. Phospholipid Metabolism: Disease, Signal Transduction, and Membrane Dynamics. Steamboat Springs, CO. June 27th, 2010. PARTICIPANTS: Undergraduate Students: Nana Sasu,Ksenia Rogalo, Hayley Hoffman, Graduate Students: Daniel Hess, Mary Nashed, Jung Kim. TARGET AUDIENCES: Target audiences: Academic: areas of nutrition, biology, physiology and biochemistry. Cancer biology and therapeutics Industry: nutrition and foods, biotechnology, pharmaceutics, drug development. Efforts: on-site laboratory instruction. Internships for undergraduate students. PROJECT MODIFICATIONS: Not relevant to this project.

Impacts
Lung cancer is the most frequent form of cancer. The survival rate for patients with metastatic lung cancer is ~5%, hence alternative therapeutic strategies to treat this disease are critically needed. Recent studies suggest that lipid biosynthetic pathways, particularly fatty acid synthesis and desaturation, are promising molecular targets for cancer therapy. We have previously reported that inhibition of stearoylCoA desaturase-1 (SCD1), the enzyme that produces monounsaturated fatty acids (MUFA), impairs lung cancer cell proliferation, survival and invasiveness, and dramatically reduces tumor formation in mice. In this report, we inform that inhibition of SCD activity in human lung cancer cells with the small molecule SCD inhibitor CVT-11127 reduced lipid synthesis and impaired proliferation by blocking the progression of cell cycle through the G1/S boundary and by triggering programmed cell death. These alterations resulting from SCD blockade were fully reversed by either oleic (18:1n-9), palmitoleic acid (16:1n-7) or cis-vaccenic acid (18:1n-7) demonstrating that cis-MUFA are key molecules for cancer cell proliferation. Additionally, co-treatment of cells with CVT-11127 and CP-640186, a specific acetylCoA carboxylase (ACC) inhibitor, did not potentiate the growth inhibitory effect of these compounds, suggesting that inhibition of ACC or SCD1 affects a common target critical for cell proliferation. Since SCD1 is downstream from ACC, MUFA is the common fatty acid product in the pathway and the deficiency in MUFA is resulting in impaired cell proliferation. This hypothesis was further reinforced by the observation that exogenous oleic acid reverses the anti-growth effect of SCD and ACC inhibitors. Finally, incubation with 25-hydroxycholesterol, a potent inhibitor of the lipogenic transcriptional factor SREBP-1 markedly reduced the proliferation of cells undergoing SCD blockade, compared to SCD inhibitor alone. Even in the presence of the SCD1 inhibitor and down-regulated lipogenesis oleic acid restored cell growth to control levels. Altogether, these observations suggest that while the anti-proliferative activity of SCD inhibitors maybe enhanced by further inhibition of lipogenesis, MUFA alone is sufficient to restore cell growth, cell cycle progression and prevent apoptosis.

Publications

• 1. Igal, R. A. Role of StearoylCoA Desaturase-1 in cell proliferation, programmed cell death and transformation to cancer. (2010)Carcinogenesis, 31:1509-15.
• 2. Hess, D., Scaglia, N., Chisholm J. W., and Igal R.A. StearoylCoA desaturase-1 regulates cell cycle progression and programmed cell death by activating lipogenesis in cancer cells (2010) Public Library of Science (PLoS) ONE 5:e11394.
• 3. Scaglia N., Chisholm, JW, and Igal, R. A. Inhibition of Stearoyl-CoA Desaturase 1 inactivates acetyl-CoA carboxylase and impairs proliferation in human cancer cells. Role of AMPK. (2009) Public Library of Science (PLoS) ONE 4, e6812.

Progress 01/01/09 to 12/31/09

Outputs
OUTPUTS: Supervision: A) Undergraduate Students: - Nana Sasu, Rutgers University Department of Nutritional Sciences. - Hayley Hoffman, University of Rochester. B) Graduate Students: - Daniel Hess, PhD student, Rutgers University Department of Nutritional Sciences. - Miho Maeda, laboratory assistant. Teaching: - Nutrition: A Biochemical and Physiological Basis (16:709:552) - Advanced Nutrition II:Energy and Micronutrient Metabolism (11:709:401) - Nutrition Seminar (16:709:601) - Nutritional Aspect of Disease, Spring (16:709:506), Rutgers University. Events: A) Lectures: 1- February, 2009, Seminar, Cancer Institute of New Jersey, Division of Medical Oncology, Title: Role of lipid metabolism in cancer: the case of Stearoyl-CoA desaturase-1, a key lipogenic enzyme. 2- February 2009, Seminar, Endocrinology and Animal Biosciences, Rutgers University, Title: Role of Lipid Metabolism in cell proliferation, survival and transformation to cancer. 3- October 2009, Seminar, Rutgers Center for Lipid Research, Rutgers University. Title: Stearoyl-CoA desaturase-1 and cancer. B): Communications in scientific meetings: 1- Molecular targets in Cancer Prevention-NIH, February 4-5, 2009, Bethesda, MD. "Inhibition of Stearoyl-CoA Desaturase 1 inactivates acetyl-CoA carboxylase and impairs proliferation in human cancer cells. Role of AMPK". Natalia Scaglia, Jeffrey Chisholm and R. Ariel Igal. 2- Gordon Research Conference, July 19-24, 2009, Waterville valley, VT. "Role of StearoylCoA desaturase-1 in the regulation of lipid metabolism and the signaling pathways that control metabolism in cancer cells". Natalia Scaglia, Daniel Hess, Jeffrey Chisholm and R. Ariel Igal. 3- AACR Conference metabolism and cancer, September 13-19, 2009, la Jolla, CA. Title: Role of StearoylCoA desaturase-1 in the regulation of lipid metabolism and the signaling pathways that control metabolism in cancer cells. Natalia Scaglia, Daniel Hess, Jeffrey Chisholm and R. Ariel Igal. Dissemination: Member, International Exchange Program, "Health Across Borders II", Rutgers University and Universidad de la Mixteca, Mexico. PARTICIPANTS: participants: Nana Sasu-Hayley Hoffman-Miho Maeda-Daniel Hess. TARGET AUDIENCES: Target audiences: Academic: areas of biology, physiology and biochemistry. Cancer biology and therapeutics. Industry: nutrition, biotechnology, pharmaceutics, drug development. Efforts: on-site laboratory instruction. Internships of undergraduate students. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.

Impacts
Cancer cells activate the biosynthesis of saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) in order to sustain an increasing demand for phospholipids with appropriate acyl composition during cell replication. We have previously shown that a stable knockdown of stearoyl-CoA desaturase 1 (SCD1), the main Δ9-desaturase that converts SFA into MUFA, in cancer cells decreases the rate of lipogenesis, reduces proliferation and in vitro invasiveness, and dramatically impairs tumor formation and growth. Here we report that pharmacological inhibition of SCD1 with a novel small molecule in cancer cells promoted the activation of AMP-activated kinase (AMPK) and the subsequent reduction of acetyl-CoA carboxylase activity, with a concomitant inhibition of glucose-mediated lipogenesis. The pharmacological inhibition of AMPK further decreased proliferation of SCD1-depleted cells, whereas AMPK activation restored proliferation to control levels. Addition of supraphysiological concentrations of glucose or pyruvate, the end product of glycolysis, did not reverse the low proliferation rate of SCD1-ablated cancer cells. Our data suggest that cancer cells require active SCD1 to control the rate of glucose-mediated lipogenesis, and that when SCD1 activity is impaired cells downregulate SFA synthesis via AMPK-mediated inactivation of acetyl-CoA carboxylase, thus preventing the harmful effects of SFA accumulation. Importantly, our findings strongly suggest a therapeutic value for small molecule inhibitors of SCD1 in the treatment of cancer.

Publications

• Scaglia N., Chisholm, J.W., Igal, R. A. Inhibition of Stearoyl-CoA Desaturase 1 inactivates acetyl-CoA carboxylase and impairs proliferation in human cancer cells. Role of AMPK. (2009) PLoS ONE 4, e6812 .

Progress 01/01/08 to 12/31/08

Outputs
OUTPUTS: Experiments: 1) Experimental model: Human cancer cells deficient in SCD1 expression and respective controls were generated by antisense strategies. Expression and activity of this enzyme was assessed. 2) Studies of lipid metabolism: determination of fatty acid composition, de novo synthesis of lipids. Analysis of signal transduction mechanisms: determination of activation of Akt pathway. Supervision: A) Undergraduate Students: - Nana Sasu, Rutgers University Department of Nutritional Sciences. - Miho Maeda, Rutgers University Department of Nutritional Sciences. George H. Cook Honors Program, 2007. B) Graduate Students: - Daniel Hess, Rutgers University Department of Nutritional Sciences. C) postdoctoral fellows: - Natalia Scaglia, Rutgers University Department of Nutritional Sciences. Teaching: - Nutrition: A Biochemical and Physiological Basis (16:709:552) - Advanced Nutrition II:Energy and Micronutrient Metabolism (11:709:401) - Nutrition Seminar (16:709:601) Events: A) Lectures: 1. Cancer Institute of New Jersey, Cancer Grand Rounds, January 21st, 2009, Title: "Role of Stearoyl-CoA desaturase-1, a key lipogenic enzyme, in cell proliferation, survival and transformation to cancer". 2. Department of Microbiology and Biochemistry, Rutgers University. November 7th, 2008. Title: "Regulation of lipid metabolism and signaling in cancer cells". 3. Institute of Biology at Rosario, National University of Rosario, Argentina, July 24th, 2008; Title: "Alpha and omega of a delta-desaturase: role of SCD-1 in cell growth, survival and transformation to cancer" 4. Princeton University, Department of Molecular Biology. February 19th, 2008. Title "Role of Stearoyl-CoA Desaturase 1 in proliferation, survival and tumorogenesis". 5. Bristol-Myers Squibb Company, NJ. February 8th, 2008. Title: "Role of Stearoyl-CoA desaturase 1 in proliferation and survival of human cancer cells". Dissemination: Member of SEBS-Rutgers faculty group, visit to the Oaxaca University System, Oaxaca, Mexico to explore collaboration between Rutgers and UTM. PARTICIPANTS: Undergraduate Students: Nana Sasu; Miho Maeda. Graduate Students: Daniel Hess. Postdoctoral fellows: - Natalia Scaglia TARGET AUDIENCES: Target audiences: Academic: areas of biology, physiology and biochemistry. Cancer biology and therapeutics Industry: biotechnology, pharmaceutics, drug development. Efforts: on-site laboratory instruction. Internships for undergraduate students. PROJECT MODIFICATIONS: Not relevant to this project.

Impacts
Lung cancer is the leading cause of cancer death in the US and one of the most deadly forms of cancer worldwide. The vast majority of lung cancer (~80%) belongs to the histopathological type of non-small cell lung cancer, with squamous cell carcinomas and adenocarcinomas as the most prominent forms. Since the 5-year survival rate of lung cancer remains disappointingly low (~14%), it is clear that a thorough understanding of the mechanisms of lung cancer development are necessary in order to discover new therapeutic targets. In this regard, lipid metabolism remains an understudied area of cancer research, although information on lipid perturbations in cancer is emerging. For instance, a ubiquitous metabolic alteration in several types of cancer cells occurs in the de novo synthesis of fatty acids, the building blocks of both cell membrane-forming phospholipids and storage lipids like triacylglycerols and cholesteryl esters. Saturated (SFA) and monounsaturated (MUFA) fatty acids, the most abundant fatty acid species, have many divergent biological effects including regulation of cell proliferation, programmed cell death, and lipid-mediated cytotoxicity. Their distribution is regulated by Stearoyl-CoA Desaturases (SCD), the enzymes that convert SFA into MUFA. A positive correlation between high levels of tissue MUFA and several types of cancer has been reported, but a causal relationship between the function of SCD1, the main human SCD isoform, and cancer development has not yet been firmly established. We demonstrated that the stable knockdown of SCD1 gene expression in A549 human lung adenocarcinoma cells decreased the ratio MUFA/SFA in total lipids and inhibited the incorporation of glucose into cell lipids. Cell proliferation and anchorage-independent growth were considerably decreased in SCD1-depleted cells, whereas the rate of apoptosis was elevated, with respect to control A549 cells. In addition, phosphorylation of Akt-Ser473 and GSK-3β-Ser9 was found notably impaired in SCD1-ablated A549 cells. Interestingly, the effects of SCD1 blockade on Akt activation, cancer cell growth and apoptosis could not be reversed by exogenously added oleic acid. Remarkably, the reduction of SCD1 expression in lung cancer cells significantly delayed the formation of tumors and reduced the growth rate of tumor xenografts in mice. Our study demonstrates that SCD1 activity regulates Akt activation and determines the rate of cell proliferation, survival and invasiveness in A549 cancer cells and shows, for the first time, that SCD1 is a key factor in the regulation of tumorigenesis in vivo. In summary, we report here that SCD1 appears to be an essential factor in the stepwise process leading to the onset and progression of lung cancer, laying the groundwork to explore the potential therapeutic applications of targeting SCD1 to treat human cancers.

Publications

• Publications: 1) Scaglia N., and Igal, R. A. .(2008) Inhibition of Stearoyl-CoA Desaturase 1 expression in human lung adenocarcinoma cells impairs tumorigenesisInternational Journal of Oncology 33, 839-850
• 2) Maeda, M., Scaglia, N., and Igal, R. A. (2008) Regulation of fatty acid synthesis and Δ9-desaturation in senescenceof human cells. Life Sciences, in press