Movement of cancer cells from the primary tumor to distant metastatic sites represents the mostlethal stage of cancer progression. The potential for a cell to migrate and invade depends on amultitude of signaling pathways, which present novel targets for anti-cancer therapies. ReactiveOxygen Species (ROS) are known modulators of tumorigenicity and act as novel secondmessengers in a multitude of cellular signaling cascades. Intrinsic levels of ROS are elevated innumerous metastatic cancer types. The ability of tumor cells to survive and thrive with anincreased ROS milieu suggests that these have evolved to utilize changes in sublethal ROS levelsto drive pro-metastatic signaling events. Our preliminary data suggest that picomolar sublethalincreases in mitochondrial derived ROS/hydrogen peroxide (H2O2) lead to a more tumorigenic,migratory and invasive phenotype in metastatic cancer cells, in vitro and in vivo. These changesin ROS lead to alterations in pro-migratory signaling cascades, following oxidation andinactivation of key phosphatases. In addition, these studies present a novel concept that H2O2 is aregulatory factor that essentially has opposing effects on membrane localization of pro- and anti-migratory signaling players. We therefore hypothesize that sub lethal increases in mitochondrialROS production regulate the spatial activation of pro-migratory signaling pathways enhancingthe metastatic potential of cancer cells. Using a metastatic bladder cancer model this will betested by: 1) Investigating the cellular site of action of mitochondrial ROS and their role inregulating oxidation and spatial distribution of Protein Tyrosine Phosphatases (PTPs) involved inmigratory signaling. 2) Determining the effects of mitochondrial ROS on mediators of FocalAdhesion Kinase signaling during migration; and 3) Assessing the consequences of enhancedintracellular ROS levels in an in vivo model of metastatic bladder cancer and the effectiveness ofantioxidant adjuvant therapy in this model. Importantly, these studies will establish a novel rolefor ROS as second messengers in regulating the spatial activation of pro-migratory signalingpathways, further our understanding of the role of mitochondrial ROS in metastatic progression;and determine the therapeutic potential of antioxidants, targeted to inhibit pro-migratorysignaling, in metastatic bladder cancer.

Public Health Relevance

This research will further our knowledge of the intracellular mechanisms thatregulate migration and invasion of tumor cells. Understanding the role of reactiveoxygen species in these events will aid in the development of novel antioxidantbased cancer therapies targeting metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
7R00CA143229-06
Application #
9036682
Study Section
Special Emphasis Panel (NSS)
Program Officer
Woodhouse, Elizabeth
Project Start
2012-09-12
Project End
2015-08-31
Budget Start
2015-03-21
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
$168,619
Indirect Cost
$57,039
Name
Pennsylvania State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Engelberth, Sarah A; Hempel, Nadine; Bergkvist, Magnus (2017) Cationic dendritic starch as a vehicle for photodynamic therapy and siRNA co-delivery. J Photochem Photobiol B 168:185-192
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Engelberth, Sarah A; Hempel, Nadine; Bergkvist, Magnus (2015) Chemically Modified Dendritic Starch: A Novel Nanomaterial for siRNA Delivery. Bioconjug Chem 26:1766-74
Dier, Usawadee; Shin, Dong-Hui; Hemachandra, L P Madhubhani P et al. (2014) Bioenergetic analysis of ovarian cancer cell lines: profiling of histological subtypes and identification of a mitochondria-defective cell line. PLoS One 9:e98479
Hempel, Nadine; Melendez, J Andres (2014) Intracellular redox status controls membrane localization of pro- and anti-migratory signaling molecules. Redox Biol 2:245-50
Engelberth, Sarah A; Hempel, Nadine; Bergkvist, Magnus (2014) Development of nanoscale approaches for ovarian cancer therapeutics and diagnostics. Crit Rev Oncog 19:281-315
Hempel, Nadine; Bartling, Toni R; Mian, Badar et al. (2013) Acquisition of the metastatic phenotype is accompanied by H2O2-dependent activation of the p130Cas signaling complex. Mol Cancer Res 11:303-12

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