Anticachectic regulator analysis reveals Perp-dependent antitumorigenic properties of 3-methyladenine in pancreatic cancer

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 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 3methyladenine (3-MA) as a candidate anti-wasting compound. In vitro analyses confirmed anti-wasting capacity while in vivo analysis revealed potent anti-tumor effects. Transcriptome analyses of 3-MA-treated tumor cells implicated Perp as a 3-MA target gene. We subsequently 1) observed significantly higher expression of Perp in cancer cell lines compared to control cells, 2) noted a survival disadvantage associated with elevated Perp, and 3) found that 3-MA-associated Perp reduction inhibited tumor cell growth. Finally, we provide 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 further implicate Perp as a tumor promoting factor in pancreatic cancer. 3 SIGNIFICANCEIneffective tumor-directed therapies and severe cachexia are two major contributors to the dismal (~10%) 5-year pancreatic cancer survival rate. Our studies uncovered 3-MA as a potent anti-tumor/anti-wasting compound and implicate Perp as a key 3-MA target gene.

Molecular signatures of inherited and acquired sporadic late onset nemaline myopathies

“…RNA integrity was verified using a Fragment Analyzer (Agilent, Santa Clara, CA). Library preparation, sequencing and analysis were performed at the Mayo Clinic Medical Genome Facility as previously described [ 21 ]. Briefly, mRNA libraries were generated using the TruSeq Stranded mRNA kit (Illumina, San Diego, CA), then pooled and sequenced on Illumina High Seq 4000 using 100 bp paired-end reads and 8 samples per lane.…”

Blocking muscle wasting via deletion of the muscle-specific E3 ubiquitin ligase MuRF1 impedes pancreatic tumor growth

“…Female experiments. Tibialis anterior harvested from female mice were placed in a sucrose sink (30%) overnight prior to freezing, sectioning and laminin staining as previously described 37 . Briefly, sections (8 μm) were fixed in 4% paraformaldehyde (PFA) for 5 minutes at room temperature prior to immunostaining.…”

“…Longitudinal body composition including lean mass and fat mass was measured via EchoMRI Body Composition Analyzer (Echo Medical Systems) as previously described 37 . Longitudinal tumor measurements were performed via caliper measurements.…”

Key Genetic Determinants Driving Esophageal Squamous Cell Carcinoma Initiation and Immune Evasion

“…6g, Extended Data 10d). Although these markers are upregulated in various cancers [35][36][37][38][39][40] , they have not been investigated in ESCC. ESCC patients with higher expression of B2M, RGS1, THEMIS2, PERP, and CD151 experienced poor survival compared to those with lower expression (Extended Data 10d).…”