Date of Award

6-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Regenerative and Rehabilitation Sciences

Research Advisor

James A. Carson, PhD

Committee

Stephen E. Alway, PhD; Evan S. Glazer, MD, PhD; Junaith S. Mohamed, PhD; Melissa Puppa, PhD

Keywords

energy metabolism; 5-fluorouracil; oxaliplatin; colorectal cancer; exercise

Abstract

Colorectal cancer patient survival rate has increased over the past decade due to improved screening and treatment options. The clinically relevant FOLFOX (5-fluorouracil [5-FU], oxaliplatin, leucovorin) chemotherapy regimen is a mainstay treatment option, despite the development of severe side-effects that can occur acutely or develop as a late effect after treatment cessation. Cancer and chemotherapy can promote systemic metabolic dysfunction; consequently, patients will likely experience debilitating weakness and fatigue, and these symptoms are often accompanied by excessive fat and muscle loss. Although studies have established chemotherapy effects on the tumor, few have investigated mechanisms underlying the metabolic complications associated with cancer and chemotherapy that may persist long after treatment completion. Using in vitro and in vivo approaches, the overall purpose of this study was to determine the role of AMPK/mTORC1 signaling in cancer and FOLFOX chemotherapy- induced metabolic dysfunction. Specifically, the AMPK/mTORC1 regulation of autophagy and protein synthesis was examined acutely after treatment, during recovery with and without exercise, and in combination with the inflammatory tumor environment in male and female mice. The hypothesis was that FOLFOX chemotherapy will suppress muscle protein synthesis and autophagy through altered AMPK/mTORC1 signaling, and these disruptions will not be readily reversible following treatment completion; AMPK activation will offset these aberrations in vitro. The results from the study reveal that FOLFOX chemotherapy induced long-lasting functional deficits that were prevented by long- (60min/d) and short-duration (15min/d) treadmill exercise training performed over two weeks during recovery from FOLFOX. Whole-body metabolic rate was suppressed in male FOLFOX treated mice up to 10-weeks after treatment cessation. These metabolic aberrations were independent of changes in cage activity and food intake. In vitro we present novel evidence that FOLFOX exerts direct effects to suppress AMPK/mTORC1 signaling, protein synthesis, and autophagy flux. AMPK activation with metformin was not sufficient to regulate autophagy flux, however, rapamycin treatment partially restored the FOLFOX-suppression of autophagy flux in myotubes. Finally, we present evidence that FOLFOX and the C26-tumor environment exert distinct effects on inflammatory and metabolic signaling. FOLFOX attenuated the C26-induction of plasma IL-6 and LIF in males but not females. FOLFOX and female sex altered the relationship between circulating cytokines to tumor and lean mass. FOLFOX suppressed muscle AMPK phosphorylation only in male muscle and this was independent of the tumor. Future studies should examine the sex hormone regulation of inflammation and metabolism during chemotherapy treatment and recovery in clinically relevant tumor models. Overall, we demonstrate effects for FOLFOX to induce persistent metabolic dysfunction that can be mitigated by a low dose of exercise and provide rationale for investigation into the therapeutic potential of rapamycin to offset chemotherapy toxicities.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

https://orcid.org/0000-0002-3174-5713

DOI

10.21007/aetd.cghs.2024.0005

Additional Files
2024-005-Halle_AETD DOA.pdf (284 kB)
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