JNK1 determines the oncogenic or tumor-suppressive activity of the integrin-linked kinase in human rhabdomyosarcoma

Abstract

Introduction Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Despite advances in multimodality therapy, the failure-free survival of patients diagnosed with metastatic RMS remains low, at 25% (1). RMS tumors are believed to arise from committed mesenchymal or myogenic progenitor cells that accumulate genetic damage and fail to terminally differentiate (2). RMS tumors largely belong to 2 different histologic subgroupings: 63% are of embryonal RMS (ERMS) histology, while nearly 20% are of alveolar RMS (ARMS) histology (2). In addition to the morphologic and ultrastructural differences between these 2 tumor histologies, they display distinct clinical profiles. ARMS tumors are more likely to be found in the extremities of older children, while ERMS tumors are more commonly found in the head and neck, trunk, and genitourinary systems of younger children (2). ARMS tumors are further associated with a poorer clinical course, exemplified by a higher incidence of bone marrow and lung metastases and higher mortality rate (2).The molecular differences between ARMS and ERMS tumors have been intensively studied (2). Of ARMS tumors, 70% display chromosomal translocations, fusing the neuromuscular development-associated genes paired box 3 (PAX3) and PAX7 to the PKB/

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

“…The ILK R211A mutation has been shown to be phenotypically null in several cancer cell lines 29,48 , and is potentially a gene therapy candidate for heart failure indications. To test the in vivo effects of ILK R211A , we measured the protein expression profile of SERCA-2a, pPLN and pCaMKII in transgenic mice with cardiacspecific overexpression of ILK R211A (ref.…”

The oncogenic and growth-suppressive functions of the integrin-linked kinase are distinguished by JNK1 expression in human cancer cells

“…17 In RMS, these independent functions demonstrate dependency on expression of the c-jun amino terminal kinase-1 (JNK1). Reduced While most reports detail an oncogenic function for the integrin-linked kinase (ILK) in human cancer, few describe a contradictory growth-suppressive function.…”

“…Recently, we demonstrated that JNK1β isoform expression levels were elevated in ERMS cells, where ILK is a tumor suppressor, compared to ARMS cells where ILK is an oncogene. 17 JNK1β1 and β2 are two of four splice isoforms transcribed from the JNK1 gene. 23,24 JNKs are stress-responsive kinases that signal to transcription factors of the activator protein-1 (AP-1) complex, stimulating proliferation, differentiation and apoptosis in a cell-type specific manner (reviewed in refs.…”

“…28). ILK interacts indirectly with the AP-1 complex, 29,30 and intriguingly, siRNAmediated depletion of JNK1 in ERMS cells, or overexpression of JNK1 in ARMS cells is sufficient to induce a switch in ILK activity, 17 indicating that JNK1 levels are critical to the determination of ILK function in RMS. As a preliminary method of investigating whether JNK1 expression levels differed in cells other than RMS where ILK functioned as a growth suppressor, compared to those in which it functioned as an oncogene, we compared the expression of JNK1 in cell lines of the NCI60 panel.…”

“…Furthermore, when cell lines were grouped based on the function of ILK, elevated levels of JNK1, JNK1β1 and JNK1β2 were found in cells in which ILK suppressed growth, compared to those in which it promoted growth JNK1 expression resulted in oncogenic function for ILK due to an inability to repress JNK1-mediated activation of the c-Jun oncogene. 17,18 Since both the oncogenic and tumor suppressive functions of ILK are dependent on its kinase activity in RMS cells 17 and bioavailable small molecule kinase inhibitors of ILK have been developed for use in vivo, 6,7,19,20 it is of critical importance to understand whether ILK may similarly function as a growth suppressor in other human malignancies. 8 To address this question, we evaluated the effect of ILK and ILK-R211A kinase mutant overexpression on proliferation and apoptosis of a panel of cancer cell lines representing different tumor types.…”