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.
|Yang, H-M; Cho, M-R; Sung, J-H et al. (2011) The effect of human fetal liver-derived mesenchymal stem cells on CD34+ hematopoietic stem cell repopulation in NOD/Shi-scid/IL-2Ra(null) mice. Transplant Proc 43:2004-8|
|Neznanov, Nickolay; Gorbachev, Anton V; Neznanova, Lubov et al. (2009) Anti-malaria drug blocks proteotoxic stress response: anti-cancer implications. Cell Cycle 8:3960-70|
|Neznanov, Nickolay; Dragunsky, Eugenia M; Chumakov, Konstantin M et al. (2008) Different effect of proteasome inhibition on vesicular stomatitis virus and poliovirus replication. PLoS One 3:e1887|
|Neznanov, Nickolay; Kondratova, Anna; Chumakov, Konstantin M et al. (2008) Quercetinase pirin makes poliovirus replication resistant to flavonoid quercetin. DNA Cell Biol 27:191-8|
|Komarova, Elena A; Krivokrysenko, Vadim; Wang, Kaihua et al. (2005) p53 is a suppressor of inflammatory response in mice. FASEB J 19:1030-2|
|Neznanov, Nickolay; Neznanova, Lubov; Angres, Brigitte et al. (2005) Serologically defined colon cancer antigen 3 is necessary for the presentation of TNF receptor 1 on cell surface. DNA Cell Biol 24:777-85|
|Neznanov, Nickolay; Chumakov, Konstantin M; Neznanova, Lubov et al. (2005) Proteolytic cleavage of the p65-RelA subunit of NF-kappaB during poliovirus infection. J Biol Chem 280:24153-8|
|Gorbacheva, Victoria Y; Kondratov, Roman V; Zhang, Renliang et al. (2005) Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/BMAL1 transactivation complex. Proc Natl Acad Sci U S A 102:3407-12|
|Lu, Tao; Burdelya, Lyudmila G; Swiatkowski, Shannon M et al. (2004) Secreted transforming growth factor beta2 activates NF-kappaB, blocks apoptosis, and is essential for the survival of some tumor cells. Proc Natl Acad Sci U S A 101:7112-7|
|Gurova, Katerina V; Gudkov, Andrei V (2003) Paradoxical role of apoptosis in tumor progression. J Cell Biochem 88:128-37|