/pdf/inositol-trisphosphate-and-diacylglycerol-as-second-4drzjsg27y.pdf

Inositol trisphosphate and diacylglycerol as second messengers.

Insulin and insulin-like growth factors (IGFs) are well known as key regulators of energy metabolism and growth. There is now considerable evidence that these hormones and the signal transduction networks they regulate have important roles in neoplasia. Epidermiological, clinical and laboratory research methods are being used to investigate novel cancer prevention and treatment strategies related to insulin and IGF signalling. Pharmacological strategies under study include the use of novel receptor-specific antibodies, receptor kinase inhibitors and AMP-activated protein kinase activators such as metformin. There is evidence that insulin and IGF signalling may also be relevant to dietary and lifestyle factors that influence cancer risk and cancer prognosis. Recent results are encouraging and have justified the expansion of many translational research programmes.

Insulin and insulin-like growth factor signalling in neoplasia

Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.

ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition

https://www.cell.com/cell/pdf/0092-8674(87)90193-0.pdf

Evidence that transforming growth factor-β is a hormonally regulated negative growth factor in human breast cancer cells

https://www.cell.com/cell/pdf/0092-8674(89)90026-3.pdf

Neural and developmental actions of lithium: A unifying hypothesis

https://www.upstate.edu/endo/pdf/researchlab/j_biol_chem_2003.pdf

Epac-selective cAMP Analog 8-pCPT-2′-O-Me-cAMP as a Stimulus for Ca2+-induced Ca2+ Release and Exocytosis in Pancreatic β-Cells

The mechanisms of steroid and peptide hormone action in human breast cancer are poorly understood. We have previously characterized a cell line of human breast cancer in long-term tissue culture that possesses various steroid hormone receptors and responses, providing a model for the study of steroid hormone action. The present studies describe a human breast cancer in vitro that responds to physiologie concentrations of insulin with an increased rate of macromolecular synthesis and growth. Thymidine and uridine incorporation in cells in serum-free medium are stimulated by 10(-11) M insulin and are maximal with 10(-8) M. Leucine incorporation is stimulated by 5 X 10(-11) M insulin and is maximal with 10(-9) M. Significant stimulation of uridine and leucine incorporation is evident by 3 hr and maximal by 10 hr. A 10-hr lag period exists for insulin stimulation of thymidine incorporation, which is maximal form 14 to 24 hr. The effect of 10(-8) M insulin on macromolecular synthesis is accompanied by a 69% increase above controls in the number of cells after 24 hr. The effect on macromolecular synthesis is observed in glucose-free medium. Insulin's effect on protein synthesis is not blocked by inhibition of RNA synthesis with actinomycin D. Glucocorticoids partially inhibit the action of insulin in these cells. This system provides a model for studying insulin action, and suggests that some human breast cancer may show growth regulation by insulin.

https://www.pnas.org/content/pnas/73/12/4536.full.pdf

Hormone responsive human breast cancer in long-term tissue culture: effect of insulin.

The malignant transformation of cells requires adaptations across multiple metabolic processes to satisfy the energy required for their increased rate of proliferation. Dysregulation of lipid metabolism has been a hallmark of the malignant phenotype; increased lipid accumulation secondary to changes in the levels of a variety of lipid metabolic enzymes has been documented in a variety of tumors, including prostate. Alterations in prostate lipid metabolism include upregulation of several lipogenic enzymes as well as of enzymes that function to oxidize fatty acids as an energy source. Cholesterol metabolism and phospholipid metabolism are also affected. With respect to lipogenesis, most studies have concentrated on increased expression and activity ofthe de novo fatty acid synthesis enzyme, fatty acid synthase (FASN), with suggestions that FASN might function as an oncogene. A central role for fatty acid oxidation in supplying energy to the prostate cancer cell is supported by the observation that the peroxisomal enzyme, α-methylacyl-CoA racemase (AMACR), which facilitates the transformation of branched chain fatty acids to a form suitable for β-oxidation, is highly overexpressed in prostate cancer compared with normal prostate. Exploitation of the alterations in lipid metabolic pathways in prostate cancer could result in the development of new therapeutic modalities as well as provide candidates for new prognostic and predictive biomarkers. AMACR has already proven to be a valuable biomarker in distinguishing normal from malignant prostate tissue, and is used routinely in clinical practice.

Lipid metabolism in prostate cancer.

Insulin interaction with four human breast cancer cell lines in tissue culture was studied with respect to specific binding to receptors, degradation, and biological responsiveness. All four lines bound and degraded 125I-labeled insulin. Binding and degradation were time, temperature, and pH dependent. Unlabeled insulin competed with 125I-labeled insulin for binding to the breast cells with half-maximal inhibition of binding being observed with less than 0.6 ng/ml for three of the four lines. Other peptides competed for insulin binding in proportion to their biological potency. Scatchard analysis of the insulin binding data revealed curvilinear plots consistent with negative cooperativity, and this was confirmed by kinetic studies of dissociation. Quantitative analysis of insulin degradation revealed a similar Km for all four cell lines (1.0 to 2.2 × 10-7m), whereas maximal velocities varied over a 7-fold range. Bacitracin, a polypeptide antibiotic, inhibited insulin degradation by all four lines. In one cell line, typical competitive binding data and Scatchard plots were obtained only after inhibition of degradation with bacitracin. Insulin stimulated precursor incorporation into macromolecules and fatty acids in only two of the four cell lines; with these, significant stimulation was seen with concentrations as low as 0.6 ng/ml. No correlation was found between the amount of specific binding, receptor concentration, or receptor affinity and the ability of insulin to stimulate the cells, suggesting a defect distal to the hormone-receptor interaction in the two unresponsive lines. The two responsive cell lines showed the most insulin degradation. These human cell lines should provide a useful tool for further study of the complex mechanisms of insulin action and for the study of factors that regulate growth of human breast cancer.

https://cancerres.aacrjournals.org/content/canres/38/1/94.full.pdf

Correlation Among Insulin Binding, Degradation, and Biological Activity in Human Breast Cancer Cells in Long-Term Tissue Culture

The effects of estrone, estradiol, and estriol on MCF-7 human breast cancer are compared. In this estrogen-responsive cell line, all three estrogens are capable of inducing equivalent stimulation of amino acid and nucleoside incorporation. Estriol is capable of partially overcoming antiestrogen inhibition with Tamoxifen (lCl 46474), even when antiestrogen is present in 1000-fold excess. Antiestrogen effects are completely overcome by 100-fold less estriol. Studies of metabolism of estrogens by MCF-7 cells revealed no conversion of estriol to either estrone or estradiol. All three steroids bind to a high-affinity estrogen receptor found in these cells. The apparent dissociation constant is lower for estradiol than for estrone and estriol, but all three bind to an equal number of sites when saturating concentrations are used. Tritiated estrogens used in binding studies were shown to be radiochemically pure. We conclude that estriol can bind to estrogen receptor and stimulate human breast cancer in tissue culture. Our data do not support an antiestrogenic role for estriol in human breast cancer.

https://cancerres.aacrjournals.org/content/canres/37/6/1901.full.pdf

Marie E. Monaco

Papers

Epac-selective cAMP Analog 8-pCPT-2′-O-Me-cAMP as a Stimulus for Ca2+-induced Ca2+ Release and Exocytosis in Pancreatic β-Cells

Hormone responsive human breast cancer in long-term tissue culture: effect of insulin.

Lipid metabolism in prostate cancer.

Correlation Among Insulin Binding, Degradation, and Biological Activity in Human Breast Cancer Cells in Long-Term Tissue Culture

Effects of Estrone, Estradiol, and Estriol on Hormone-responsive Human Breast Cancer in Long-Term Tissue Culture