Cancer incidence increases exponentially with age, suggesting that a common mechanism contributes to both of these biological processes. One such mechanism is thought to be oxidative stress, due to an imbalance between the production of reactive oxygen species (ROS, e.g. O2.- and H2O2, arising from O2 metabolism), and their removal by the antioxidant network. A majority of aging-research is focused on understanding the mechanisms regulating replicative lifespan (Hayflick limit), which is attributed to telomere shortening and mitotic attrition. In the previous period of support (R01 CA111365), we discovered a novel mode of cellular aging (chronological lifespan), which is independent of both mitotic attrition and telomerase activity. We define chronological lifespan as the duration in which quiescent cells retain their capacity to re-enter the proliferative cycle and transit back to quiescence. Our data show that molecular and pharmacologically induced overexpression of manganese superoxide dismutase (MnSOD) suppresses age-associated increase in mitochondrial injury, and extends chronological lifespan. We also observed that MnSOD overexpression inhibits age-associated increases in the ability of quiescent fibroblasts to stimulate the proliferation of neighboring epithelial cancer cells. Finally, our recent preliminary results suggest that MnSOD-induced regulation of cell cycle regulatory pathways including the redox-sensitive phosphatase, DUSP1, and the chemokine, CCL5, could mediate chronological lifespan in human fibroblasts. These observations have now led us to test the specific hypothesis that MnSOD and ROS (O2.- and H2O2) regulate the chronological lifespan of human fibroblasts as well as their ability to influence the proliferation of epithelial cancer cells via edox-sensitive cell cycle regulatory pathways involving DUSP1 and CCL5. To investigate this hypothesis we will determine if: (a) MnSOD dependent expression of DUSP1 and CCL5 regulates the chronological lifespan of normal human fibroblasts;(b) cellular quiescence and redox-sensitive post-transcriptional mechanisms regulate MnSOD, DUSP1, and CCL5 expression;and (c) the aging of quiescent fibroblasts regulates the proliferation of epithelial cancer cells in co-cultures via the secretion of CCL5. A better understanding of the redox-biology of chronological lifespan and its effect on epithelial cancer progression will be of significance to aging and cancer research because this knowledge can greatly facilitate the development of novel nutritional and antioxidant-based approaches to promote healthy aging and suppress age-related cancer progression.

Public Health Relevance

An understanding of the redox-biology of chronological lifespan will be of significance to aging and cancer research because this knowledge can greatly facilitate the development of novel nutritional and antioxidant- based approaches to promote healthy aging and suppress age-related cancer progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA111365-06A1
Application #
8371105
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Okano, Paul
Project Start
2004-12-01
Project End
2017-05-31
Budget Start
2012-08-01
Budget End
2013-05-31
Support Year
6
Fiscal Year
2012
Total Cost
$208,203
Indirect Cost
$70,320
Name
University of Iowa
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Sibenaller, Zita A; Welsh, Jessemae L; Du, Changbin et al. (2014) Extracellular superoxide dismutase suppresses hypoxia-inducible factor-1? in pancreatic cancer. Free Radic Biol Med 69:357-66
Sarsour, Ehab H; Goswami, Monali; Kalen, Amanda L et al. (2014) Hydroxytyrosol inhibits chemokine C-C motif ligand 5 mediated aged quiescent fibroblast-induced stimulation of breast cancer cell proliferation. Age (Dordr) 36:9645
Eckers, Jaimee C; Kalen, Amanda L; Sarsour, Ehab H et al. (2014) Forkhead box M1 regulates quiescence-associated radioresistance of human head and neck squamous carcinoma cells. Radiat Res 182:420-9
Xiao, Wusheng; Zhu, Yueming; Sarsour, Ehab H et al. (2013) Selenoprotein P regulates 1-(4-Chlorophenyl)-benzo-2,5-quinone-induced oxidative stress and toxicity in human keratinocytes. Free Radic Biol Med 65:70-7
Eckers, Jaimee C; Kalen, Amanda L; Xiao, Wusheng et al. (2013) Selenoprotein P inhibits radiation-induced late reactive oxygen species accumulation and normal cell injury. Int J Radiat Oncol Biol Phys 87:619-25
Sarsour, Ehab H; Kumar, Maneesh G; Kalen, Amanda L et al. (2012) MnSOD activity regulates hydroxytyrosol-induced extension of chronological lifespan. Age (Dordr) 34:95-109
Chaudhuri, L; Nicholson, A M; Kalen, A L et al. (2012) Preferential selection of MnSOD transcripts in proliferating normal and cancer cells. Oncogene 31:1207-16
Venkatesha, Venkatasubbaiah A; Kalen, Amanda L; Sarsour, Ehab H et al. (2010) PCB-153 exposure coordinates cell cycle progression and cellular metabolism in human mammary epithelial cells. Toxicol Lett 196:110-6
Chaudhuri, Leena; Sarsour, Ehab H; Goswami, Prabhat C (2010) 2-(4-Chlorophenyl)benzo-1,4-quinone induced ROS-signaling inhibits proliferation in human non-malignant prostate epithelial cells. Environ Int 36:924-30
Sarsour, Ehab H; Goswami, Monali; Kalen, Amanda L et al. (2010) MnSOD activity protects mitochondrial morphology of quiescent fibroblasts from age associated abnormalities. Mitochondrion 10:342-9

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