Effects of parathyroid hormone-related protein and macrophage inflammatory protein-1α in Jurkat T-cells on tumor formationin vivoand expression of apoptosis regulatory genesin vitro

Abstract

Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1α (MIP-1α) have been implicated in the pathogenesis of adult T-cell leukemia/lymphoma, but their effects on T-cells have not been well studied. Here we analyzed the functions of PTHrP and MIP-1α on T-cell growth and death both in vitro and in vivo by overexpressing either factor in human Jurkat T-cells. PTHrP or MIP-1α did not affect Jurkat cell growth in vitro, but PTHrP increased their sensitivity to apoptosis. Importantly, PTHrP and MIP-1α decreased both tumor incidence and growth in vivo. To investigate possible mechanisms, polymerase chain reaction (PCR) arrays and real-time reverse transcription (RT)-PCR assays were performed. Both PTHrP and MIP-1α increased the expression of several factors including signal transducer and activator of transcription 4, tumor necrosis factor α, receptor activator of nuclear factor κB ligand and death-associated protein kinase 1, and decreased the expression of inhibitor of DNA binding 1, interferon γ and CD40 ligand in Jurkat cells. In addition, MIP-1α also increased the expression of transcription factor AP-2α and PTHrP increased expression of the vitamin D3 receptor. These data demonstrate that PTHrP and MIP-1α exert a profound antitumor effect presumably by increasing the sensitivity to apoptotic signals through modulation of transcription and apoptosis factors in T-cells.

Twenty-five years of PTHrP progress: From cancer hormone to multifunctional cytokine

“…A major contributor to this co-operation is tumor production of PTHrP, together with the several other cancer-derived factors that influence bone metastasis establishment, including prostaglandins and cytokines (96) and of factors favoring the homing and/or adherence of cancer cells to bone (99). Although this emphasizes PTHrP involvement in breast cancer, increasing evidence implicates it in prostate, lung, renal, colon, lymphoid and other cancers (100–104). …”

Meta-Analysis of HTLV-1-Infected Patients Identifies CD40LG and GBP2 as Markers of ATLL and HAM/TSP Clinical Status: Two Genes Beat as One

“…Decision tree analysis revealed genes CD40LG and GBP2 as discriminators of ATLL and HAM/TSP, offering accuracy rates of 100% and 84.2%, respectively. A previous report identified lower CD40LG expression in cells expressing PTHrP and MIP-1α, two proteins associated with ATLL progression (Shu et al, 2012). The second marker identified herein, GBP2 , was previously associated with tax protein activity in HTLV-1 (Arainga et al, 2012).…”

Parathyroid hormone-related protein promotes bone loss in T-cell leukemia as well as in solid tumors

“…Human T cell leukemia Jurkat cell line with stable transfection of PTHrP, MIP-1α, or pcDNA3.1 vector and luciferase expression were previously generated and characterized [24]. These three cell lines Jurkat-pcDNA-luc, Jurkat-PTHrP-luc, and Jurkat-MIP-1α-luc will be referred to as Jurkat-pcDNA, Jurkat-PTHrP, or Jurkat-MIP-1α throughout this paper.…”

“…Real-time RT-PCR (qRT-PCR) was used to confirm expression levels of PTHrP and MIP-1α mRNA for this study (not shown; see ref. [24] for original figure). Secretion of PTHrP in Jurkat-PTHrP cells was confirmed by immunoassay at the Diagnostic Center for Population and Animal Health at Michigan State University {Jurkat-PTHrP (42.4 pmol/l)}.…”

“…PTHrP and MIP-1α are two factors that have demonstrated a significant role in endocrinemediated bone resorption and HHM but the paracrine role of these factors in ATL remains unknown. To investigate the individual contributions of PTHrP and MIP-1α on local osteolysis, we made use of cell lines that we had previously generated and used for an intraperitoneal injection study [24].…”