ag-490 and Body-Weight

Cancer cachexia syndrome is observed in 80% of patients with advanced-stage cancer, and it is one of the most frequent causes of death. Severe wasting accounts for more than 80% in patients with advanced pancreatic cancer. Here we wanted to define, by using an microarray approach and the Pdx1-cre;LSL-Kras(G12D) ;INK4a/arf(fl/fl) mice model, the pathways involved in muscle, liver, and white adipose tissue wasting. These mice, which develop systematically pancreatic cancer, successfully reproduced many human symptoms afflicted with this disease, and particularly cachexia. Using the profiling analysis of pancreatic cancer-dependent cachectic tissues we found that Jak2/Stat3 pathways, p53 and NFkB results activated. Thus, our interest was focused on the Jak2 pathways because it is pharmacologically targetable with low toxicity and FDA approved drugs are available. Therefore, Pdx1-cre;LSL-Kras(G12D) ;INK4a/arf(fl/fl) mice were treated with the Jak2 inhibitor AG490 compound daily starting at 7 weeks old and for a period of 3 weeks and animals were sacrificed at 10 weeks old. Body weight for control mice was 27.84 ± 2.14 g, for untreated Pdx1-cre;LSL-Kras(G12D) ;INK4a/arf(fl/fl) was 14.97 ± 1.99 g, whereas in animals treated with the AG490 compound the weight loss was significantly less to 24.53 ± 2.04 g. Treatment with AG490 compound was efficient since phosphorylation of Jak2 and circulating interleukin-6 (IL6) levels were significantly reduced in cachectic tissues and in mice respectively. In conclusion, we found that Jak2/Stat3-dependent intracellular pathway plays an essential role since its pharmacological inhibition strongly attenuates cachexia progression in a lethal transgenic pancreatic cancer model.

Topics: Adenocarcinoma; Adipose Tissue, White; Animals; Body Weight; Cachexia; Gene Expression Profiling; Interleukin-6; Janus Kinase 2; Liver; Mice; Mice, Transgenic; Muscle, Skeletal; Pancreatic Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Signal Transduction; STAT3 Transcription Factor; Time Factors; Tyrphostins

To investigate the effects of the JAK2/STAT3 pathway on skeletal muscle development and energy metabolism, AG490 and IL-11 were used as agonist and inhibitor in treating mice and the mouse skeletal muscle cells. Average body weight (ABW) was reduced significantly in the mice treated with AG490 (p<0.05), while IL-11 had the opposite effect (p<0.05), as compared with the controls, average body temperature (ABT) remained at normal levels in both groups. Western blotting was used to determine the protein levels of JAK2, STAT3, p-JAK2, and p-STAT3. AG490 caused significant decreases in p-JAK2 and p-STAT3 (p<0.05), while IL-11 did the opposite (p<0.05, p<0.01). Quantitative RT-PCR also showed significantly decreased expression levels of Myf5, MyoD, LXRa, and UCP3 in the AG490 group (p<0.01), but in the IL-11 group, the expression of Myf5, MyoD, and UCP3 was increased (p<0.05), except that LXRa whose expression did not change. In cultured skeletal muscle cells, the expression of MyoD, Myf5, LXRa, and UCP3 (p<0.05) exhibited the same trend as that in the skeletal muscles of both treated groups (p<0.05). These results implicate the JAK2/STAT3 in skeletal muscle development and energy metabolism.

Topics: Animals; Body Composition; Body Temperature; Body Weight; Energy Metabolism; Gene Expression Regulation, Developmental; Interleukin-11; Janus Kinase 2; Male; Mice; Muscle, Skeletal; Signal Transduction; STAT3 Transcription Factor; Tyrphostins