1. ¹Center for Childhood Cancer, Columbus Children's Research Institute, Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA
2. ²Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43205, USA
3. ³Division of Medical Technology, School of Allied Medical Professions, The Ohio State University, Columbus, OH 43205, USA
4. ⁴Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43205, USA
5. ⁵Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43205, USA

Correspondence: Dr J Lin, Center for Childhood Cancer, Columbus Children's Research Institute, The Ohio State University, Columbus, OH 43205, USA; E-mail: lin.674@osu.edu

Received 17 January 2007; Revised 25 July 2007; Accepted 31 July 2007.

Abstract

Rhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sarcoma including two major subtypes, alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS). Increasing evidence suggests that oncogenesis of RMS involves multistages of signalling protein dysregulation which may include prolonged activation of serine/threonine kinases such as phosphoinositide-dependant kinase-1 (PDK-1) and AKT. To date, whether PDK-1/AKT pathway is activated in RMS is unknown. This study was to examine phosphorylation status of AKT and to evaluate a novel small molecular inhibitor, OSU-03012 targeting PDK-1 in RMS. We examined phosphorylation levels of AKT using ARMS and ERMS tissue microarray and immunohistochemistry staining. Our results showed phospho-AKT^Thr308 level is elevated 42 and 35% in ARMS and ERMS, respectively. Phospho-AKT^Ser473 level is also increased 43% in ARMS and 55% in ERMS. Furthermore, we showed that OSU-03012 inhibits cell viability and induces apoptosis in ARMS and ERMS cell lines (RH30, SMS-CTR), which express elevated phospho-AKT levels. Normal cells are much less sensitive to OSU-03012 and in which no detectable apoptosis was observed. This study showed, for the first time, that PDK-1/AKT pathway is activated in RMS and may play an important role in survival of RMS. PDK-1/AKT pathway may be an attractive therapeutic target for cancer intervention in RMS using OSU-03012.