Biology subjects

Rheinheimer, B. A.

Publications and source records attributed to Rheinheimer, B. A..

3 recordsLinked to original sources

bioRxiv2023

Radiation-Induced Changes in Energy Metabolism Result in Mitochondrial Dysfunction in Salivary Glands

Salivary glands are indirectly damaged during radiotherapy for head and neck cancer, resulting in acute and chronic hyposalivation. Current treatments for radiation-induced hyposalivation do not permanently restore function to the gland; therefore, more mechanistic understanding of the damage response is needed to identify therapeutic targets for lasting restoration. Energy metabolism reprogramming has been observed in cancer and wound healing models to provide necessary fuel for cell proliferation; however, there is limited understanding of alterations in energy metabolism reprogramming in tissues that fail to heal. We measured extracellular acidification and oxygen consumption rates, assessed mitochondrial DNA copy number, and tested fuel dependency of irradiated primary salivary acinar cells. Radiation treatment leads to increases in glycolytic flux, oxidative phosphorylation, and ATP production rate at acute and intermediate time points. In contrast, at chronic radiation time points there is a significant decrease in glycolytic flux, oxidative phosphorylation, and ATP production rate. Irradiated salivary glands exhibit significant decreases in spare respiratory capacity and increases in mitochondrial DNA copy number at days 5 and 30 post-treatment, suggesting a mitochondrial dysfunction phenotype. These results elucidate kinetic changes in energy metabolism reprogramming of irradiated salivary glands that may underscore the chronic loss of function phenotype.

molecular biology↗

bioRxiv2022

AMPK activation restores salivary function following radiation treatment

Head and neck cancers represent a significant portion of cancer diagnoses, with head and neck cancer incidence increasing in some parts of the world. Typical treatment of early-stage head and neck cancers includes either surgery or radiotherapy; however, advanced cases often require surgery followed by radiation and chemotherapy. Salivary gland damage following radiotherapy leads to severe and chronic hypofunction with decreased salivary output, xerostomia, impaired ability to chew and swallow, increased risk of developing oral mucositis, and malnutrition. There is currently no standard of care for radiation-induced salivary gland dysfunction and treatment is often limited to palliative treatment that provides only temporary relief. AMP-activated protein kinase (AMPK) is an enzyme that activates catabolic processes and has been shown to influence the cell cycle, proliferation, and autophagy. In the present study, we found that radiation (IR) treatment decreases tissue levels of phosphorylated AMPK following radiation and decreases intracellular NAD+ and AMP while increasing intracellular ATP. Further, expression of Sirtuin-1 (SIRT1) and nicotinamide phosphoribosyl transferase (NAMPT) were lower five days following IR. Treatment with AMPK activators, AICAR and metformin, attenuated compensatory proliferation (days 6, 7 and 30) following IR, and reversed chronic (day 30) salivary gland dysfunction post-IR. Additionally, treatment with metformin or AICAR increased markers of apical/basolateral polarity (phosphorylated aPKC{zeta}T560 positive area) and differentiation (amylase positive area) within irradiated parotid glands to levels similar to untreated controls. Taken together, these data suggest that AMPK may be a novel therapeutic target for treatment of radiation-induced salivary damage.

molecular biology↗

bioRxiv2020

Cell intrinsic signaling in MEN1 mutant pancreatic neuroendocrine tumors unveils novel signaling pathways associated with de-differentiation

ObjectivesPreliminary genomic analysis of primary pancreatic neuroendocrine tumors revealed a complex mutational landscape with four common oncogenic events; however, critical activation pathways responsible for pancreatic neuroendocrine tumor progression and metastasis have yet to be elucidated. Here, we analyzed six primary pancreatic neuroendocrine tumors to determine which pathways are deregulated and responsible for progression. MethodsSelected genomic profiling of six primary pancreatic neuroendocrine tumors was performed using the Ion Torrent Comprehensive Cancer Panel with matched transcriptomes analyzed by Affymetrix Clariom D arrays. Validation of gene expression changes were measured by quantitative PCR using TaqMan assays and immunohistochemistry on tumor specimens. ResultsMEN1 was mutated in half (50%) of our sequenced tumors while FGFR3 was mutated in 2/6 (33%). Transcriptome analysis revealed that ITGA2 and EZH2 were overexpressed in MEN1 mutant tumors whereas ALK and VEGFA were overexpressed in FGFR3 mutant tumors. Immunohistochemistry revealed increased nuclear ITGA2 and EZH2 staining along with increased VE-Cadherin staining and loss of membranous E-cadherin localization in MEN1 and FGFR3 mutant tumors. ConclusionsOur results suggest that pancreatic neuroendocrine tumors containing MEN1 and FGFR3 mutations are more aggressive and de-differentiated than their wild-type counterparts. Additionally, we provide novel chemotherapeutic target FGFR3 for patients with this disease.

cancer biology↗