Janus kinase inhibitors suppress cancer cachexia-associated anorexia and adipose wasting in mice

Abstract

Background

Cachexia, a syndrome of muscle atrophy, adipose loss, and anorexia, is associated with reduced survival in cancer patients. The colon adenocarcinoma C26c20 cell line secretes the cytokine leukaemia inhibitory factor (LIF), which induces cachexia. We characterized how LIF promotes cachexia-associated weight loss and anorexia in mice through Janus kinase (JAK)-dependent changes in adipose and hypothalamic tissues.

Methods

Cachexia was induced in vivo with the heterotopic allotransplanted administration of C26c20 colon adenocarcinoma cells or the intraperitoneal administration of recombinant LIF in the absence or presence of JAK inhibitors. Blood, adipose, and hypothalamic tissues were collected and processed for cytokine/adipokine enzyme-linked immunosorbent assays, immunoblot analysis, and quantitative reverse transcription polymerase chain reaction (RT-PCR). Cachexia-associated lipolysis was induced in vitro by stimulating differentiated adipocytes with recombinant LIF or interleukin (IL)-6 in the absence or presence of lipase or JAK inhibitors. These adipocytes were processed for glycerol release into the media, immunoblot analysis, and RT-PCR.

Results

Tumour-secreted LIF induced changes in adipose tissue expression and serum levels of IL-6 and leptin in a JAK-dependent manner influencing cachexia-associated adipose wasting and anorexia. We identified two JAK inhibitors that block IL-6 family-mediated adipocyte lipolysis and IL-6 induction using an in vitro cachexia lipolysis assay. JAK inhibitors administered to the in vivo C26c20 cancer cachexia mouse models led to (i) a decrease in signal transducer and activator of transcription 3 phosphorylation in hypothalamic and adipose tissues, (ii) a reverse in the cachexia serum cytokine/adipokine signature, (iii) a delay in cancer cachexia-associated anorexia and adipose loss, and (iv) an improvement in overall survival.

Conclusions

JAK inhibitors suppress LIF-associated adipose loss and anorexia in both in vitro and in vivo models of cancer cachexia.