Graduation Date

Spring 5-4-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Dr. Pankaj K. Singh

Abstract

Pancreatic cancer is the third-leading cause of cancer-related deaths in the United States. About 80 percent of the pancreatic cancer patients suffer from cachexia and, about one-third die due to complexities related to the syndrome. Cachexia leads to a loss in body weight and cachectic patients are refractory to chemotherapy. Despite recent advances, the mechanisms of pancreatic cancer- cachexia and the potential therapeutic interventions remain poorly evaluated.

Sirtuins represent a class of proteins that are regulated by metabolic fluctuations in tissues. We observed a reduced expression of Sirt1 in spontaneous PDAC mice muscles, human pancreatic cancer muscles, and myotubes treated by cancer cell-conditioned media. We further observed that cancer cell-conditioned media upregulated the NF-κB and FoxO transcription factor pathways. NF-κB regulated the expression of NADPH Oxidase (Nox4) in cachectic muscles, thereby increasing reactive oxygen species (ROS). We also observed a negative correlation between Nox4 expression and muscle cross-sectional area in the cachectic muscles of PDAC patients. Inducible genetic knockout of Nox4 gene in muscles of tumor-bearing mice rescued the cachectic phenotype. Moreover, pharmacological blockade of Nox4 activity was successful in attenuating loss in body weight and muscle mass in tumor-bearing mice. Therefore, we concluded that the Sirt1-Nox4 axis plays an important role in the manifestation of pancreatic cancer cachexia.

Studies have shown that chemotherapy in addition to tumor burden can induce body weight loss in cancer patients. We performed a single-center retrospective study of 162 patients at our institution by measuring muscle mass among patients with a diagnosis of pancreatic cancer at initial diagnosis and eight-week follow up post treatment. We found a significant improvement in overall survival and progression-free survival in patients with modest or no reduction in skeletal muscle index after eight weeks of chemotherapy. Furthermore, we treated mice with Gemcitabine and FOLFIRINOX, and observed a decrease in body weight, gastrocnemius muscle weight, grip-strength, and rotarod performance. We also observed an increase in chemotherapy-induced ROS in the mice. We observed that utilizing BMX-001, a SOD mimetic rescued the decrease in body weight, muscle weight, grip-strength, and rotarod performance in mice treated with chemotherapy. BMX-001 was also successful in rescuing chemotherapy-induced muscle wasting in tumor-bearing mice. We concluded that targeting ROS production in skeletal muscles could prevent chemotherapy-induced muscle wasting.

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