The long-term goal of this research project is to better understand the role of melatonin derived from the pineal gland, in conjunction with phytomelatonin ingested in the diet, in the prevention of the growth of human malignancies in the context of biological timing. Melatonin inhibition of tissue-isolated tumor (rat hepatoma 7288CTC) growth in vivo occurs via inhibitory G protein-coupled melatonin receptor-mediated suppression of cAMP and a resultant blockade of tumor linoleic acid (LA) uptake and 13-hydroxyoctadecadienoic acid (13-HODE). This occurs via inhibition of fatty acid transport protein (FATP) function. 13-HODE, which amplifies the epidermal growth factor EGF-mitogenic signaling pathway, is the mitogenic signal responsible for LA-dependent tumor growth. The hypothesis to be tested is: Melatonin, derived from the pineal gland and dietary sources, plays a significant role in the prevention of human tumor development and growth; the mechanism of action is via melatonin receptor-mediated suppression of cAMP-dependent FATP function and/or expression leading to a blockade of tumor LA uptake and production of 13-HODE in the context of circadian time structure.
The first aim i s to assess the effects of dietary melatonin on tissue-isolated human tumor growth and LA metabolism in vivo.
The second aim i s to further define the melatonin signal transduction mechanisms involved in the regulation of tissue-isolated tumor LA metabolism and growth in vivo.
The third aim i s to examine the interactions among FATP function, melatonin inhibitory signaling, and EGF stimulatory signaling in the control of tissue-isolated tumor LA metabolism and growth.
The fourth aim i s to further define the circadian rhythm regulation of FA metabolism simultaneously in tissue-isolated tumors and contralateral fat pads and the role of melatonin. The proposed studies will help to provide a scientific rationale for the development of new dietary recommendations that consider LA intake, circadian-timed melatonin supplementation and/or photoperiodic alterations for the prevention and treatment of cancer growth and cachexia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076197-05
Application #
6513144
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Milner, John A
Project Start
1997-09-15
Project End
2005-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
5
Fiscal Year
2002
Total Cost
$279,938
Indirect Cost
Name
Mary Imogene Bassett Hospital
Department
Type
DUNS #
City
Cooperstown
State
NY
Country
United States
Zip Code
13326
Blask, David E; Hill, Steven M; Dauchy, Robert T et al. (2011) Circadian regulation of molecular, dietary, and metabolic signaling mechanisms of human breast cancer growth by the nocturnal melatonin signal and the consequences of its disruption by light at night. J Pineal Res 51:259-69
Sauer, Leonard A; Blask, David E; Dauchy, Robert T (2007) Dietary factors and growth and metabolism in experimental tumors. J Nutr Biochem 18:637-49
Dauchy, Robert T; Dauchy, Erin M; Davidson, Leslie K et al. (2007) Inhibition of fatty acid transport and proliferative activity in tissue-isolated human squamous cell cancer xenografts perfused in situ with melatonin or eicosapentaenoic or conjugated linoleic acids. Comp Med 57:377-82
Smith, Laura C; Dauchy, Erin M; Dauchy, Robert T et al. (2006) Dietary fish oil deactivates a growth-promoting signaling pathway in hepatoma 7288CTC in Buffalo rats. Nutr Cancer 56:204-13
Dauchy, Erin M; Dauchy, Robert T; Davidson, Leslie K et al. (2006) Human cancer xenograft perfusion in situ in rats: a new perfusion system that minimizes delivery time and maintains normal tissue physiology and responsiveness to growth-inhibitory agents. J Am Assoc Lab Anim Sci 45:38-44
Blask, David E; Dauchy, Robert T; Sauer, Leonard A (2005) Putting cancer to sleep at night: the neuroendocrine/circadian melatonin signal. Endocrine 27:179-88
Blask, David E; Brainard, George C; Dauchy, Robert T et al. (2005) Melatonin-depleted blood from premenopausal women exposed to light at night stimulates growth of human breast cancer xenografts in nude rats. Cancer Res 65:11174-84
Sauer, Leonard A; Dauchy, Robert T; Blask, David E et al. (2005) Eicosapentaenoic acid suppresses cell proliferation in MCF-7 human breast cancer xenografts in nude rats via a pertussis toxin-sensitive signal transduction pathway. J Nutr 135:2124-9
Dauchy, Robert T; Dauchy, Erin M; Sauer, Leonard A et al. (2004) Differential inhibition of fatty acid transport in tissue-isolated steroid receptor negative human breast cancer xenografts perfused in situ with isomers of conjugated linoleic acid. Cancer Lett 209:7-15
Sauer, Leonard A; Dauchy, Robert T; Blask, David E et al. (2004) Conjugated linoleic acid isomers and trans fatty acids inhibit fatty acid transport in hepatoma 7288CTC and inguinal fat pads in Buffalo rats. J Nutr 134:1989-97

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