Abstract
Approximately 80% of pancreatic cancer patients suffer from cachexia, and one-third die due to cachexia-related complications such as respiratory failure and cardiac arrest. Although there has been considerable research into cachexia mechanisms and interventions, there are, to date, no FDA-approved therapies. A major contributing factor for the lack of therapy options could be the failure of animal models to accurately recapitulate the human condition. In this study, we generated an aged model of pancreatic cancer cachexia to compare cachexia progression in young versus aged tumor-bearing mice. Comparative skeletal muscle transcriptome analyses identified 3-methyladenine (3-MA) as a candidate antiwasting compound. In vitro analyses confirmed antiwasting capacity, while in vivo analysis revealed potent antitumor effects. Transcriptome analyses of 3-MA–treated tumor cells implicated Perp as a 3-MA target gene. We subsequently (a) observed significantly higher expression of Perp in cancer cell lines compared with control cells, (b) noted a survival disadvantage associated with elevated Perp, and (c) found that 3-MA–associated Perp reduction inhibited tumor cell growth. Finally, we have provided in vivo evidence that survival benefits conferred by 3-MA administration are independent of its effect on tumor progression. Taken together, we report a mechanism linking 3-MA to Perp inhibition, and we further implicate Perp as a tumor-promoting factor in pancreatic cancer.
Highlights
Pancreatic cancer is the third leading cause of cancer-related deaths in the United States
Given that the median age of diagnosis of pancreatic cancer is 70, it reasons that therapeutic targets identified based on molecular changes observed in young mouse models of cancer cachexia might not translate effectively to an aged human population
We observed a reduction in mean myotube diameter of C2C12 cells treated with T4-KPC conditioned media (CM) and T3-KPC CM (P = 0.0069 and 0.0018, respectively) compared with those treated with MS1 CM (Figure 1A)
Summary
Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. Cachexia is not often listed as a primary cause of death, it is widely understood that patients experiencing weight and muscle loss have worse prognoses than those who do not [3, 4]. Significant progress has been made toward identifying fundamental mechanisms of cancer cachexia, FDA-approved therapies are lacking [5]. Major reasons for the lack of effective therapies are likely rooted in fundamental differences between animal models and the human condition [6]. Given that the median age of diagnosis of pancreatic cancer is 70, it reasons that therapeutic targets identified based on molecular changes observed in young mouse models of cancer cachexia might not translate effectively to an aged human population
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