Pancreatic cancer and cachexia : effects of leucine and HMB supplementation

Pancreatic cancer has the highest mortality rate of all major cancers with a 5-year survival rate of 8%. A major contributor to this statistic is the lean muscle loss that occurs with cachexia, a condition found in 80% of pancreatic cancer patients. The effects of two potential cachexia treatments—the branched-chain amino acid, leucine, and its metabolite, [beta]-hydroxy-[beta]-methylbutyrate (HMB)—have been analyzed in multiple studies. However, most of these studies have determined their effects on muscle tissue only, while their effects on pancreatic tumor growth remain unknown. The objective of this current study was to evaluate the impact of dietary leucine and HMB supplementation on pancreatic ductal adenocarcinoma (PDAC) in pro-tumor and anti-tumor environments and identify potential mechanisms of inhibition or enhancement. Using C57BL/6 male mice, we demonstrated that dietary leucine supplementation enhanced pancreatic tumor growth in both the pro-tumor environment of overweight mice and the anti-tumor environment of lean mice. Leucine supplementation increased the amount of circulating glucose available for the tumor in the overweight mice, while it increased tumor mechanistic target of rapamycin (mTOR) activation in the lean mice. Next, we determined that dietary HMB supplementation preserved muscle mass through increased muscle mTOR activation. HMB supplementation also inhibited pancreatic tumor growth and enhanced the efficacy of the chemotherapy gemcitabine in the pro-tumor environment of obese C57BL/6 mice. HMB supplementation downregulated numerous olfactory receptor genes that were upregulated in the tumors of obese mice, and HMB also increased cytotoxic CD8+ T cell infiltration in these tumors. Additional experiments were conducted to determine the potential mechanisms for the effects of leucine and HMB on pancreatic cancer. We showed leucine supplementation increased, while HMB supplementation decreased, both human and murine pancreatic cancer cell proliferation and mTOR signaling. Leucine and HMB also had differential effects on the regulation of certain olfactory receptor genes, and octanal, an olfactory receptor agonist, could mimic the repressive effects of HMB supplementation on pancreatic cancer cell proliferation. Collectively, these findings suggest that HMB has the most potential for cancer cachexia treatment due to its ability to preserve muscle mass, reduce tumor growth, and enhance the effects of chemotherapy. The in vivo results suggest leucine and HMB can affect tumor indirectly by manipulating physiology, and the in vitro findings suggest they can also affect cancer cells directly.