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LORNE HOFSETH, PhD
Hofseth
LJ, Robles AI, Espey MG, and Harris CC. Nitric oxide is a
signaling molecule that regulates gene expression. Methods
in Enzymology, in press
Nitric oxide (NO2) is a dynamic and
bio-reactive molecule that can both participate in and
inhibit the genesis of disease. Its ability to impact a wide
range of physiological events stems from its capacity to
reversibly alter the expression of specific genes and the
activities of a wide range of proteins and signaling
pathways. Yet, NO2 remains an enigmatic molecule. Recently
developed technologies, including gene-chips, 2D
electrophoresis, RNA interference, MALDI-TOF mass
spectrometry, and protein arrays will allow us to better
understand how NO2 and associated reactive nitrogen species
(RNS) regulate both physiology and disease states, toward
the development of treatments using NO2 synthase inhibitors
or NO2 donors.
Hofseth LJ. The adaptive imbalance to
genotoxic stress: genome guardians rear their ugly heads.
Carcinogenesis. 2004 Oct;25(10):1787-93. Epub 2004 May 27.
Review.
An adaptive response of the
genome-protection machinery occurs in cells exposed to
genotoxic stress. This machinery includes the p53 and
retinoblastoma protein pathways, which are not mutually
exclusive from other adapting machinery including DNA
repair, cell cycle checkpoints, apoptosis and endogenous
metabolizing and antioxidant enzymes. The adaptive changes
occur in chronic inflammation and in cigarette smokers
associated with a high cancer risk, and are an attempt to
keep cells healthy. However, there is increasing evidence
that this response may have deleterious effects. Here, key
pathways that adaptively respond to genotoxic stress are
reviewed and mechanisms by which this response may have
pro-carcinogenic implications are discussed.
Hofseth LJ, Robles AI, Yang Q, Wang XW,
Hussain SP, Harris C. p53: at the crossroads of molecular
carcinogenesis and molecular epidemiology. Chest. 2004
May;125(5 Suppl):83S-5S.
Physicians have long recognized that
people differ in their susceptibility to disease. As early
as the fifth century, Hippocrates wrote "Some men have
constitutions that are like wooded mountains running with
springs, others like those with poor soil and little water,
still others like land rich in pastures and marshes, and yet
others like the bare, dry earth of the plain." Today, we
describe these observations as interindividual variation in
disease risk manifested as gene-environment interactions, a
notion embodying the concept that heritable traits modify
the effects of environmental exposures. The heritable
effects of genes in human cancer pathogenesis range from
high penetrance with an attendant high likelihood of causing
cancer to low-penetrant genes with an attendant increased
risk of causing cancer, albeit less likely than that for
high-penetrant genes. Nevertheless, the range from low-penetrant
to high-penetrant genes is a continuum, and studies in
animal models indicate that the effects of highly penetrant
genes can be modified by other genes. In humans, high-penetrant
genes that cause family cancer syndromes can have a
substantial impact in the affected families (eg, Li-Fraumeni
syndrome involving germline mutations in the p53 tumor
suppressor pathway), but they affect only a small percentage
of the population. In contrast, the manifestations of cancer
susceptibility genes with less penetrance contribute to
common sporadic cancers and, thus, affect a large segment of
the population.
Hofseth LJ, Hussain SP, Harris CC.
p53: 25 years after its discovery. Trends Pharmacol Sci.
2004 Apr;25(4):177-81. Review.
Since its discovery 25 years ago, the p53
protein has emerged as a key tumor suppressor protein at the
crossroads of cellular stress response pathways. Through
these pathways, which can lead to cell-cycle arrest, DNA
repair, cellular senescence, differentiation and apoptosis,
p53 facilitates the repair and survival of damaged cells or
eliminates severely damaged cells from the replicative pool
to protect the organism. Because of these dynamic and
multiple functions of p53, which are largely lost following
mutations in the gene encoding p53, this molecule continues
to be studied intensively in biomedical research, including
the fields of toxicology and pharmacology. In this article,
we briefly review the first 25 years of research on p53.
Ying L, Hofseth AB, Browning DD, Nagarkatti M, Nagarkatti PS, Hofseth LJ. Nitric oxide inactivates the retinoblastoma pathway in chronic inflammation. Cancer Res. 2007 Oct 1;67(19):9286-93.
Patients with chronic inflammatory bowel disease have a high risk of colon cancer. The molecules that initiate and promote colon cancer and the cancer pathways altered remain undefined. Here, using in vitro models and a mouse model of colitis, we show that nitric oxide (NO) species induce retinoblastoma protein (pRb) hyperphosphorylation and inactivation, resulting in increased proliferation through the pRb-E2F1 pathway. NO-driven pRb hyperphosphorylation occurs through soluble guanylyl cyclase/guanosine 3',5'-cyclic monophosphate signaling and is dependent on the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase MEK/ERK and phosphatidylinositol 3-kinase/AKT pathways. Our results reveal a link between NO and pRb inactivation and provide insight into molecules that can be targeted in the prevention of the inflammation-to-cancer sequence.
Ying L, Hofseth LJ. An emerging role for endothelial nitric oxide synthase in chronic inflammation and cancer. Cancer Res. 2007 Feb 15;67(4):1407-10.
Nitric oxide (NO) is a free radical that is involved in carcinogenesis. Recent literature indicates that endothelial NO synthase (eNOS) can modulate cancer-related events (angiogenesis, apoptosis, cell cycle, invasion, and metastasis). We review the literature linking eNOS to carcinogenesis to encourage future research assessing the role of eNOS in cancer prevention and treatment.
Hofseth LJ, Wargovich MJ. Inflammation, cancer, and targets of ginseng. J. Nutr. 2007 Jan;137(1 Suppl):183S-185S.
Chronic inflammation is associated with a high cancer risk. At the molecular level, free radicals and aldehydes, produced during chronic inflammation, can induce deleterious gene mutation and posttranslational modifications of key cancer-related proteins. Other products of inflammation, including cytokines, growth factors, and transcription factors such as nuclear factor kappaB, control the expression of cancer genes (e.g., suppressor genes and oncogenes) and key inflammatory enzymes such as inducible nitric oxide synthase and cyclooxygenase-2. These enzymes in turn directly influence reactive oxygen species and eicosanoid levels. The procancerous outcome of chronic inflammation is increased DNA damage, increased DNA synthesis, cellular proliferation, disruption of DNA repair pathways and cellular milieu, inhibition of apoptosis, and promotion of angiogenesis and invasion. Chronic inflammation is also associated with immunosuppression, which is a risk factor for cancer. Current treatment strategies for reactive species overload diseases are frequently aimed at treating or preventing the cause of inflammation. Although these strategies have led to some progress in combating reactive species overload diseases and associated cancers, exposure often occurs again after eradication, treatment to eradicate the cause fails, or the treatment has long-term side effects. Therefore, the identification of molecules and pathways involved in chronic inflammation and cancer is critical to the design of agents that may help in preventing the progression of reactive species overload disease and cancer associated with disease progression. Here, we use ginseng as an example of an anti-inflammatory molecule that targets many of the key players in the inflammation-to-cancer sequence.
Hofseth LJ, Robles AI, Espey MG, Harris CC. Nitric oxide is a signaling molecule that regulates gene expression. Methods Enzymol. 2005;396:326-40.
Nitric oxide (NO) is a dynamic and bioreactive molecule that can both participate in and inhibit the genesis of disease. Its ability to have an impact on a wide range of physiological events stems from its capacity to reversibly alter the expression of specific genes and the activities of a wide range of proteins and signaling pathways. Yet, NO remains an enigmatic molecule. Recently developed technologies, including gene-chips, two-dimensional electrophoresis, RNA interference, matrix-assisted laser desorption ionization (MALDI)-TOF (time-of-flight) mass spectrometry, and protein arrays will allow us to better understand how NO and associated reactive nitrogen species (RNS) regulate both physiology and disease states, toward the development of treatments using NO* synthase inhibitors or NO donors.
Ying L, Marino J, Hussain SP, Khan MA, You S, Hofseth AB, Trivers GE, Dixon DA, Harris CC, Hofseth LJ. Chronic inflammation promotes retinoblastoma protein hyperphosphorylation and E2F1 activation. Cancer Res. 2005 Oct 15;65(20):9132-6.
Chronic inflammation contributes to tumorigenesis. The retinoblastoma protein (pRb), in its hyperphosphorylated form, releases E2 promoter binding factor-1 (E2F1), which drives cell proliferation. Here, we show that pRb is hyperphosphorylated in both mouse and human colitis. In turn, pRb hyperphosphorylation is associated with release of E2F1 from pRb, resulting in the activation of E2F1 target molecules involved in proliferation and apoptosis. These observations provide insight into the in vivo mechanisms associated with chronic colon inflammation and increased colon cancer risk.
Hofseth LJ, Ying L. Identifying and defusing weapons of mass inflammation in carcinogenesis. Biochim Biophys Acta. 2006 Jan;1765(1):74-84. Epub 2005 Sep 8.
The continued cancer risks associated with chronic inflammation necessitate the identification of inflammatory molecules and the cancer pathways they affect. Evidence indicates that there are multiple mechanisms linking inflammation to cancer and that there are multiple targets for chemoprevention. Here, we review some of the key factors and the cancer pathways they disturb as a necessary prerequisite to the identification of targets for chemoprevention.
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