Cancer Usurps Skeletal Muscle as an Energy Repository

Abstract

Cancer cells produce energy through aerobic glycolysis, but contributions of host tissues to cancer energy metabolism are unclear. In this study, we aimed to elucidate the cancer-host energy production relationship, in particular, between cancer energy production and host muscle. During the development and progression of colorectal cancer, expression of the secreted autophagy-inducing stress protein HMGB1 increased in the muscle of tumor-bearing animals. This effect was associated with decreased expression of pyruvate kinase PKM1 and pyruvate kinase activity in muscle via the HMGB1 receptor for advanced glycation endproducts (RAGE). However, muscle mitochondrial energy production was maintained. In contrast, HMGB1 addition to colorectal cancer cells increased lactate fermentation. In the muscle, HMGB1 addition induced autophagy by decreasing levels of active mTOR and increasing autophagy-associated proteins, plasma glutamate, and 13 C-glutamine incorporation into acetyl-CoA. In a mouse model of colon carcinogenesis, a temporal increase in HMGB1 occurred in serum and colonic mucosa with an increase in autophagy associated with altered plasma free amino acid levels, increased glutamine, and decreased PKM1 levels. These differences were abolished by administration of an HMGB1 neutralizing antibody. Similar results were obtained in a mouse xenograft model of human colorectal cancer. Taken together, our findings suggest that HMGB1 released during tumorigenesis recruits muscle to supply glutamine to cancer cells as an energy source.

Ovarian tumor-initiating cells display a flexible metabolism

“…There were no differences in fatty acid synthesis from 14 C-glucose between MOSE-L cells and TICs (Figure 3A) but an increase in TICs compared to MOSE-E (p=0.067). This was expected since cancer cells can activate lipolysis in adjacent white adipose tissue[31] and glutamine production in adjacent muscle tissue[32] and utilize these substrates rather than enhance their de novo synthesis; this correlates well with changes in the expression of transporters (see below). With the decrease in total oxidation seen in TICs, we next assessed the lactate levels in the medium after the 3 h incubation period with the labeled isotopes.…”

HMGB1 in health and disease

“…In addition to AGE, RAGE binds HMGB1, S100, amyloid-β peptide, DNA, RNA, and other molecules to regulate multiple physiological and pathological processes. A number of studies demonstrate that RAGE is required for HMGB1-induced cell migration (Degryse et al, 2001; Fages et al, 2000; Palumbo and Bianchi, 2004; Palumbo et al, 2004), proliferation (Kang et al, 2010), regeneration (Degryse et al, 2001; Sorci et al, 2004), inflammation (He et al, 2012b; Lv et al, 2009; Treutiger et al, 2003; Wu et al, 2013c), autophagy (Kang et al, 2012a; Weiner and Lotze, 2012), injury (Huang et al, 2012c; Wolfson et al, 2011), metabolism (Kang et al, 2014; Luo et al, 2014), and immunity (Leblanc et al, 2014). In addition, extracellular HMGB1 can stimuli RAGE expression in several cell types (Li et al, 1998).…”

“…The interaction between HMGB1 and Beclin-1 is positively regulated by ULK1 (Huang et al, 2012a), MAPK (Tang et al, 2010b), and NAC (Cheng et al, 2013), but negatively regulated by p53 (Livesey et al, 2012a) and synuclein (Song et al, 2014). Extracellular HMGB1 in its reduced form promotes autophagy through binding to RAGE (Tang et al, 2010a), which may contribute to lactate production and glutamine metabolism for tumor growth (Luo et al, 2014). Indeed, RAGE is a positive regulator of autophagy and a negative regulator of apoptosis during chemotherapy, oxidative stress, DNA damage, and hypoxia (Kang et al, 2011d; Kang et al, 2010).…”

Aerobic exercise training as therapy for cardiac and cancer cachexia

“…In fact, recent advances in molecular and cell biology have provided a high spectrum of novel drug targets, such as the ActRIIB pathway [100], the adipose triglyceride lipase or hormone-sensitive lipase [25], the HMGB1 protein [62] and the tumor-derived parathyroidhormone-related protein [52]. However, the current lack of success for a single therapy indicates that cancer cachexia intervention may include different approaches, including non-pharmacological strategies, such as AET ( [32]; [5,90]).…”