Studies of tumor resistance and sensitivity to anti-cancer therapy is largely limited to the analysis of intrinsic mechanisms of cell response to treatment. However, tumor response also involves paracrine effects, including interactions of tumor cells with each other, with the stroma and with factors released by distant tissues. Here we propose a program of studies that is aimed at the determination of the role and mechanisms of cell-cell communication in drug and radiation treatment. It is based on two lines of preliminary observations. First, by using the genetic suppressor element (GSE) technology, ubiquitous kinesin heavy chain (uKHC) was identified as a drug-sensitivity gene, deregulation of which results in an unusual type of drug resistance. More recently, it was found that normal and tumor cells under conditions of stress secrete in a p53-dependent manner growth inhibitory factors causing negative paracrine regulation (""""""""bystander effect""""""""), affecting growth of neighboring cells. Preliminary data were generated showing that kinesin-mediated drug resistance is determined by modulation of the bystander effect, suggesting that kinesin participates in p53-dependent stress-induced secretion of growth inhibitors. Current program is devoted to characterization of the role of stress-induced bystander effect in tumor response to anticancer treatment, identification of factors determining this phenomenon and the analysis of molecular mechanisms and consequences of deregulation of p53- and kinesin-mediated secretion.
Specific aims i nclude: (i) the establishment of experimental approaches and model systems to study the role of stress- dependent bystander effect in vitro and in vivo, (ii) the analysis of involvement of the kinesin function in the p53-dependent bystander effect in drug- or radiation- treated cell populations, (iii) identification of cellular proteins involved in stress-induced kinesin-mediated bystander effect, and (iv) isolation and characterization of cellular factor(s) determining stress- induced bystander effect in tumor sensitivity and resistance to therapeutic treatments and in identification of molecular determinants of this form of therapy response.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA088071-05
Application #
6744070
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Forry, Suzanne L
Project Start
2000-06-09
Project End
2005-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
5
Fiscal Year
2004
Total Cost
$275,400
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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