This project will continue our long term interest in investigating the mechanisms of control of lung cancer cell behavior, focusing on ras/raf-mediated signal transduction pathways. We have shown that raf activation can induce growth arrest in small cell lung cancer (SCLC), but not in non small cell lung cancer (NSCLC), This growth arrest is accompanied by induction of cyclin dependent kinase inhibitor expression; in at least some cell lines, p27Kip1 is induced by translational control. We hypothesize!) that raf activation may mediate growth arrest via translational control in SCLC cells, 2) that this growth arrest can be blocked by activation of rho family protein signal transduction, which may be more active in NSCLC than in SCLC cells, and 3) raf effects on SCLC cells may be mediated in part by autocrine or paracrine mechanisms. The level of activation of the rho family signal transduction pathway will be examined in SCLC and NSCLC cells. In a complementary series of studies, the effect of activating or inhibiting rho family signal transduction in SCLC cells will be investigated, focusing on the effects of rho family members on raf-mediated growth arrest. The mechanism of induction of p27kip1 by translational activation during raf-mediated growth arrest in SCLC cells will be investigated. The role of the translation initiation factor eIF4E will be examined. The ability of translational activation to induce cyclin dependent kinase inhibitors and cell cycle arrest in SCLC cells will be determined. The role of autocrine ligands in mediating the effects of raf activation in SCLC cells will be investigated. Identification of two raf-induced autocrine lung cancer derived factors, LCDF I and LCDF2, will be completed. LCDF 1 induces Phosphorylation of MAPK and accumulation of p27, and LCDF2 induces morphological changes in SCLC cells. The ability of LCDF I to promote growth arrest will be determined. The receptor for LCDF 1 will be isolated, and its signal transduction pathways will be identified. The expression patterns for LCDF 1 and its receptor, and LCDF2, will be determined in lung cancer cell lines and primary tumors. The factors responsible for raf-mediated induction of LCDF 1 in SCLC cells will be identified.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085567-03
Application #
6633658
Study Section
Pathology B Study Section (PTHB)
Program Officer
Blair, Donald G
Project Start
2001-06-01
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
3
Fiscal Year
2003
Total Cost
$339,263
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Wissing, Michel D; Dadon, Tikva; Kim, Eunice et al. (2014) Small-molecule screening of PC3 prostate cancer cells identifies tilorone dihydrochloride to selectively inhibit cell growth based on cyclin-dependent kinase 5 expression. Oncol Rep 32:419-24
Feldmann, Georg; Mishra, Anjali; Bisht, Savita et al. (2011) Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models. Cancer Biol Ther 12:598-609
Feldmann, Georg; Mishra, Anjali; Hong, Seung-Mo et al. (2010) Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling. Cancer Res 70:4460-9
Strock, Christopher J; Park, Jong-In; Nakakura, Eric K et al. (2006) Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells. Cancer Res 66:7509-15
Kim, Eun-Joo; Park, Jong-In; Nelkin, Barry D (2005) IFI16 is an essential mediator of growth inhibition, but not differentiation, induced by the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cells. J Biol Chem 280:4913-20
Park, Jong-In; Strock, Christopher J; Ball, Douglas W et al. (2005) Interleukin-1beta can mediate growth arrest and differentiation via the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cells. Cytokine 29:125-34
Nakakura, Eric K; Sriuranpong, Virote R; Kunnimalaiyaan, Muthusamy et al. (2005) Regulation of neuroendocrine differentiation in gastrointestinal carcinoid tumor cells by notch signaling. J Clin Endocrinol Metab 90:4350-6
Park, Jong-In; Powers, James F; Tischler, Arthur S et al. (2005) GDNF-induced leukemia inhibitory factor can mediate differentiation via the MEK/ERK pathway in pheochromocytoma cells derived from nf1-heterozygous knockout mice. Exp Cell Res 303:79-88
Strock, Christopher J; Park, Jong-In; Rosen, Mark et al. (2003) CEP-701 and CEP-751 inhibit constitutively activated RET tyrosine kinase activity and block medullary thyroid carcinoma cell growth. Cancer Res 63:5559-63
Park, Jong-In; Strock, Christopher J; Ball, Douglas W et al. (2003) The Ras/Raf/MEK/extracellular signal-regulated kinase pathway induces autocrine-paracrine growth inhibition via the leukemia inhibitory factor/JAK/STAT pathway. Mol Cell Biol 23:543-54