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Phosphorylation profiling and targeting of oncogenic signaling proteins in cancer cells

Cen, Ling
http://rave.ohiolink.edu/etdc/view?acc_num=osu1186666790

Abstract Details

2007, Doctor of Philosophy, Ohio State University, Ohio State Biochemistry Program.
Increasing evidence suggests that oncogenesis of malignancies involves multi-stages of signaling protein dysregulation characterized by prolonged activation of oncogenic proteins. Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma including two major subtypes, alveolar (ARMS) and embryonal rhabdomyosarcoma (ERMS). To better understand protein dysregulation events in RMS, we examined the phosphorylation profiles of multiple tyrosine and serine/threonine kinases. Our study demonstrated that phosphorylation levels of tyrosine kinases were elevated between 24% and 71% in RMS. We also showed that levels of p-AKT Thr308 and p-AKT Ser473 were increased around 40%. In addition, p-mTOR and its downstream targets, p-p70S6K, p-S6, and p-4E-BP1, were increased between 50% and 72% in both subtypes of RMS. Phosphorylation levels of PKC isozymes were upregulated between 43% and 72%. Furthermore, activated AKT pathway in RMS was blocked by a novel small molecule inhibitor OSU-03012 targeting PDK1, an upstream regulator of AKT. OSU-03012 inhibited cell viability dose- and time-dependently in ARMS and ERMS cells which have elevated p-AKT levels. It was also found that OSU-03012 induced apoptosis in RMS cells indicated by positive cleaved caspase-3 staining. In contrast, normal fibroblast cells HFF is much less sensitive to OSU-03012 treatment in which no detectable cleaved caspase-3 was observed. These results indicated that PDK1/AKT pathway is crucial for cell growth and survival of RMS and it may serve as an attractive therapeutic target for cancer intervention in RMS using OSU-03012. In addition, phosphorylation level of oncogenic protein Stat3 was found to be increased in 27% of RMS and 19% of bladder cancer tissues. Inhibition of constitutively active Stat3 pathway was achieved through applying STA-21, a small molecule inhibitor of Stat3. STA-21 inhibited cell viability and induced apoptosis in RMS and bladder cancer cells with elevated p-Stat3. Furthermore, down-regulation of anti-apoptotic genes (survivin, Bcl-2 and Bcl-XL) and cell cycle regulating gene cyclin D1 were associated with the apoptosis. This evidence indicated that activation of Stat3 play an important role in the cell survival and inhibition of constitutively active Stat3 signaling emerges as a potential therapeutic approach for treatment of rhabdomyosarcoma and bladder cancer.
Jiayuh Lin (Advisor)

Recommended Citations

Citations

  • Cen, L. (2007). Phosphorylation profiling and targeting of oncogenic signaling proteins in cancer cells [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1186666790

    APA Style (7th edition)

  • Cen, Ling. Phosphorylation profiling and targeting of oncogenic signaling proteins in cancer cells. 2007. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1186666790.

    MLA Style (8th edition)

  • Cen, Ling. "Phosphorylation profiling and targeting of oncogenic signaling proteins in cancer cells." Doctoral dissertation, Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1186666790

    Chicago Manual of Style (17th edition)

osu1186666790
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© 2007, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.