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Role of PPAR, in hepatocarcinogenesis
CONFERENCE
76 tion of tumor-promoting PGF$. In contrast, the long-chain w-3 PUFA do not stimulate COX expression, PGE, synthesis, or breast cancer progression or metastasis. Interestingly, the less aggressive estrogen receptor-positive (estrogen-dependent) human breast cancer MCF-7 cell line exhibits high basal expression of the COX1 isoform and low rates of PG& production, even in the absence of linoleic acid.
Robert Hardy, Ph.D., University of Alabama at Birmingham: Fatty Acids and Breast Cancer Cell Proliferation. Long-chain saturated fatty acids have been shown to inhibit epidermal growth factor (EGF) -induced cell proliferation in cultured human breast cancer cells. Stearate (18 carbons) completely inhibits EGF-induced cell proliferation, palmitate (16 carbons) is less inhibitory, and myristate ( 14 carbons) is not inhibitory. Data from recently completed studies suggest that stearate and palm&ate inhibit EGF-induced breast cancer cell growth via inhibition of an EGF receptor/G-protein signaling pathway.
DIETARY
FAT AND SIGNAL TRANSDUCTION
KennethHonn, Ph.D., Wayne State University School of Medicine: Lipoxygenases: Role in Metastasis and Apoptosis. Successful tumor cell invasion of the endothelial basement membrane requires adhesion, proteolytic degradation, and extravasation. All three steps are stimulated by cathepsin B, which is secreted by metastatic tumor cells following binding of a product of normal lipoxygenase metabolism of arachidonic and linoleic acids, 12 ( S ) -hydroxyeicosatetraenoic acid ( 12 ( S ) HETE) , to a specific tumor cell membrane receptor. Following 12( S)-HETE binding, a second messenger cascade is triggered resulting in activation of phospholipase C, synthesis of inositol triphosphate, activation of protein kinase C (PKC,), translocation of PKC, to the plasma membrane, synthesis of cathepsin B, synthesis of integrin and its translocation to the cell membrane, formation of focal adhesion plaques, stimulation of cell motility, hydrolysis of extracellular matrix components, and inhibition of Bcl-2 synthesis. These sequelae to routine linoleic acid metabolism and 12 ( S ) -HETE binding combine to facilitate tumor cell extravasation and invasion while suppressing apoptosis and extending tumor cell life.
Robert Chapkin, Ph.D., Texas A & M University: Select Dietary Fats and Fibers Block Carcinogen-Induced Alterations of Colonic Intracellular Secondary Messengers. Specific dietary fats (especially the fish oils) protect against colon cancer. In colonocytes, w-3 PUFA suppress carcinogen-induced rus activation, blocking the second messenger cascade. Carcinogen-associated increase in intracellular diacylglycerol concentration is prevented, as is diacylglycerol-induced malignant transformation and proteolytic degradation of PKC. Maintenance of PKC activity is required to suppress cell proliferation and sustain colonocyte differentiation and apoptotic rhythms. In animal studies, dietary fish oils decreased the incidence of colonic tumors following azoxymethane injection.
Craig D. Albright, Ph.D., University of North Carolina at Chapel Hill: Diet, Apoptosis and Carcinogenesis. Long-term choline deficiency induces hepatic carcinogenesis even in the absence of identifiable carcinogens. It is hypothesized that choline-deficiency carcinogenesis involves repeated episodes of cell death, with survival and proliferation of cell clones adapted to choline deficiency. Acute choline deficiency increases the
REVIEW
production of reactive oxygen species (especially hydroxyl radicals) and induces hepatocyte death. In contrast, hepatocytes adapted to low choline resist hydroxyl radical-induced apoptosis. Choline deficiency appears to induce mutations in growth-factor signaling pathways, which may enhance cell survival in low-choline environments, facilitate resistance to apoptosis, and predispose to malignant transformation.
DIETARY FAT AND PEROXISOME
PROLIFERATOR-ACTIVATED
RECERORS
Frank J. Gonzalez, Ph.D., National Cancer Institute: Role of PPAR, in Hepatocarcinogenesis. Peroxisome proliferators (PPs) bind to a cytosolic
steroid receptor, PP-activated receptor complex (acting as a ligand-induced transcription factor) stimulates the transcription of genes associated with the formation of new peroxisomes. Mice lacking PPAR, both fail to produce peroxisomes and do not become cancerous in the presence of PPs. Among different species, resistance to PP-stimulated carcinogenesis appears to be inversely proportional to liver content of PPAR,; hepatic PPAR, content is much lower in humans than in rodents, and PPs induce hepatic cancer in rodents but not in humans. It is hypothesized that in the presence of damaged DNA, the target gene products of the PP-activated PP/PPAR, complex inhibit apoptosis and stimulate the proliferation of cells with DNA damage, which are predisposed to malignant transformation.
(PPAR,) . The PP/PPAR,
Soner Altiok, Ph.D., Dana-Farber Cancer Institute: PPAR,Mediated Growth Regulation. Activation of PP-binding PPAR, by PUFA can initiate adipocyte hypertrophy. In so doing, PPAR, blocks cell proliferation by inhibiting the expression of proteins that bind to DNA and stimulate DNA replication, even in the presence of known carcinogens. Interestingly, activators of PPAR, currently are being tested clinically for their antineoplastic properties.
Daniel Noonan, Ph.D., University of Kentucky: Dietary Fat as a Mediator of Carcinogenesis. It is hypothesized that PPAR,, when activated by fatty acids, stimulates the transcription of peroxisomal beta-oxidation enzymes. Consequently, all of the following are stimulated: (I) beta-oxidation of free fatty acids; (2) production of acetyl-CoA; (3) production of oxygen-free radicals; (4) oxidative damage to DNA; (5) synthesis of famesyl-PP i from acetyl-CoA; (6) binding of farnesyl-PP i to farnesyl receptor; and (7) inhibition of apoptosis by activated farnesyl-complexes. These processes eventually result in hepatic carcinogenesis.
DIETARY
FAT AND GENE EXPRESSION
John Barnard, M.D., Vanderbilt University: Regulation of Intestinal Gene Expression by Short-Chain Fatty Acids. The short-chain fatty acids acetate, butyrate, and propionate, derived from colonic fermentation of dietary fiber, are the most abundant intraluminal solutes in the colon. Butyrate (but not acetate or propionate) inhibits the proliferation of colonocytes early in the Gl phase of the cell cycle by inhibiting transcription of the c-myc protooncogene. Because c-myc is known to inhibit cell differentiation and apoptosis, and over 70% of cancerous colonocytes have been found to overexpress c-myc, inhibition of c-myc expression may explain the acceleration in colonocyte
76 tion of tumor-promoting PGF$. In contrast, the long-chain w-3 PUFA do not stimulate COX expression, PGE, synthesis, or breast cancer progression or metastasis. Interestingly, the less aggressive estrogen receptor-positive (estrogen-dependent) human breast cancer MCF-7 cell line exhibits high basal expression of the COX1 isoform and low rates of PG& production, even in the absence of linoleic acid.
Robert Hardy, Ph.D., University of Alabama at Birmingham: Fatty Acids and Breast Cancer Cell Proliferation. Long-chain saturated fatty acids have been shown to inhibit epidermal growth factor (EGF) -induced cell proliferation in cultured human breast cancer cells. Stearate (18 carbons) completely inhibits EGF-induced cell proliferation, palmitate (16 carbons) is less inhibitory, and myristate ( 14 carbons) is not inhibitory. Data from recently completed studies suggest that stearate and palm&ate inhibit EGF-induced breast cancer cell growth via inhibition of an EGF receptor/G-protein signaling pathway.
DIETARY
FAT AND SIGNAL TRANSDUCTION
KennethHonn, Ph.D., Wayne State University School of Medicine: Lipoxygenases: Role in Metastasis and Apoptosis. Successful tumor cell invasion of the endothelial basement membrane requires adhesion, proteolytic degradation, and extravasation. All three steps are stimulated by cathepsin B, which is secreted by metastatic tumor cells following binding of a product of normal lipoxygenase metabolism of arachidonic and linoleic acids, 12 ( S ) -hydroxyeicosatetraenoic acid ( 12 ( S ) HETE) , to a specific tumor cell membrane receptor. Following 12( S)-HETE binding, a second messenger cascade is triggered resulting in activation of phospholipase C, synthesis of inositol triphosphate, activation of protein kinase C (PKC,), translocation of PKC, to the plasma membrane, synthesis of cathepsin B, synthesis of integrin and its translocation to the cell membrane, formation of focal adhesion plaques, stimulation of cell motility, hydrolysis of extracellular matrix components, and inhibition of Bcl-2 synthesis. These sequelae to routine linoleic acid metabolism and 12 ( S ) -HETE binding combine to facilitate tumor cell extravasation and invasion while suppressing apoptosis and extending tumor cell life.
Robert Chapkin, Ph.D., Texas A & M University: Select Dietary Fats and Fibers Block Carcinogen-Induced Alterations of Colonic Intracellular Secondary Messengers. Specific dietary fats (especially the fish oils) protect against colon cancer. In colonocytes, w-3 PUFA suppress carcinogen-induced rus activation, blocking the second messenger cascade. Carcinogen-associated increase in intracellular diacylglycerol concentration is prevented, as is diacylglycerol-induced malignant transformation and proteolytic degradation of PKC. Maintenance of PKC activity is required to suppress cell proliferation and sustain colonocyte differentiation and apoptotic rhythms. In animal studies, dietary fish oils decreased the incidence of colonic tumors following azoxymethane injection.
Craig D. Albright, Ph.D., University of North Carolina at Chapel Hill: Diet, Apoptosis and Carcinogenesis. Long-term choline deficiency induces hepatic carcinogenesis even in the absence of identifiable carcinogens. It is hypothesized that choline-deficiency carcinogenesis involves repeated episodes of cell death, with survival and proliferation of cell clones adapted to choline deficiency. Acute choline deficiency increases the
REVIEW
production of reactive oxygen species (especially hydroxyl radicals) and induces hepatocyte death. In contrast, hepatocytes adapted to low choline resist hydroxyl radical-induced apoptosis. Choline deficiency appears to induce mutations in growth-factor signaling pathways, which may enhance cell survival in low-choline environments, facilitate resistance to apoptosis, and predispose to malignant transformation.
DIETARY FAT AND PEROXISOME
PROLIFERATOR-ACTIVATED
RECERORS
Frank J. Gonzalez, Ph.D., National Cancer Institute: Role of PPAR, in Hepatocarcinogenesis. Peroxisome proliferators (PPs) bind to a cytosolic
steroid receptor, PP-activated receptor complex (acting as a ligand-induced transcription factor) stimulates the transcription of genes associated with the formation of new peroxisomes. Mice lacking PPAR, both fail to produce peroxisomes and do not become cancerous in the presence of PPs. Among different species, resistance to PP-stimulated carcinogenesis appears to be inversely proportional to liver content of PPAR,; hepatic PPAR, content is much lower in humans than in rodents, and PPs induce hepatic cancer in rodents but not in humans. It is hypothesized that in the presence of damaged DNA, the target gene products of the PP-activated PP/PPAR, complex inhibit apoptosis and stimulate the proliferation of cells with DNA damage, which are predisposed to malignant transformation.
(PPAR,) . The PP/PPAR,
Soner Altiok, Ph.D., Dana-Farber Cancer Institute: PPAR,Mediated Growth Regulation. Activation of PP-binding PPAR, by PUFA can initiate adipocyte hypertrophy. In so doing, PPAR, blocks cell proliferation by inhibiting the expression of proteins that bind to DNA and stimulate DNA replication, even in the presence of known carcinogens. Interestingly, activators of PPAR, currently are being tested clinically for their antineoplastic properties.
Daniel Noonan, Ph.D., University of Kentucky: Dietary Fat as a Mediator of Carcinogenesis. It is hypothesized that PPAR,, when activated by fatty acids, stimulates the transcription of peroxisomal beta-oxidation enzymes. Consequently, all of the following are stimulated: (I) beta-oxidation of free fatty acids; (2) production of acetyl-CoA; (3) production of oxygen-free radicals; (4) oxidative damage to DNA; (5) synthesis of famesyl-PP i from acetyl-CoA; (6) binding of farnesyl-PP i to farnesyl receptor; and (7) inhibition of apoptosis by activated farnesyl-complexes. These processes eventually result in hepatic carcinogenesis.
DIETARY
FAT AND GENE EXPRESSION
John Barnard, M.D., Vanderbilt University: Regulation of Intestinal Gene Expression by Short-Chain Fatty Acids. The short-chain fatty acids acetate, butyrate, and propionate, derived from colonic fermentation of dietary fiber, are the most abundant intraluminal solutes in the colon. Butyrate (but not acetate or propionate) inhibits the proliferation of colonocytes early in the Gl phase of the cell cycle by inhibiting transcription of the c-myc protooncogene. Because c-myc is known to inhibit cell differentiation and apoptosis, and over 70% of cancerous colonocytes have been found to overexpress c-myc, inhibition of c-myc expression may explain the acceleration in colonocyte