# Understanding the link between high-fructose intake and pancreatic cancer development

> **NIH NIH R03** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $78,750

## Abstract

Project Summary
Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies with a 5-year survival
rate of only 6% and is expected to become the second most common cause of cancer-related death in the
United States by 2030. Genetic factors are thought to be responsible for only 10 % of all PDAC cases. Several
risk factors greatly increase the likelihood that premalignant lesions will progress to PDAC, including tobacco
smoking, obesity, alcohol consumption and chronic pancreatitis. Recent epidemiological studies have shown a
relationship between high fructose intake and pancreatic cancer. Main sources of fructose in our diet are cane
sugar (sucrose) and high-fructose corn syrup, a common sweetener that has primarily replaced sucrose. The
specific mechanism whereby high fructose intake may affect PDAC development remains speculative. We fed
mice expressing oncogenic Kras high fructose diet, which resulted in increased number of preneoplastic
lesions, tumor incidence, inflammation and fibrosis and induced expression of enzymes of glycolysis and the
pentose phosphate pathway (PPP), both of which show increased rates in cancer. Interestingly, the levels of
signaling adaptor p62 that is often up regulated in cancer were also increased in pancreata of these mice
comparing to their littermates fed isocaloric control diet rich in cornstarch. p62 is a key driver of malignant
conversion, whose accumulation promotes tumorigenesis in several tumor types such as hepatoma, non-
small-cell-lung cancer, breast cancer and PDAC. In addition to binding poly-ubiquitinated protein aggregates
and targeting them for degradation by autophagy, p62 is a signaling adaptor that promotes activation of NF-κB
and NRF2 transcription factors and mTORC1. Given that both, NRF2 and mTOR pathways were shown to
control pancreatic intraepithelial neoplasia1 (PanIN1) to PDAC progression and to redirect glucose into
anabolic pathways glycolysis and PPP, we postulated that high fructose intake may stimulate PanIN1 to PDAC
progression via p62-NRF2 and p62-mTOR cascades. The aim of this project is to elucidate the mechanisms
that link increased fructose consumption to pancreatic cancer and the role of p62 in this process. In summary,
this study should provide novel insights into high fructose intake-mediated PDAC development and help create
awareness about the health risks of high fructose intake ultimately resulting in decreased PDAC incidence and
mortality.

## Key facts

- **NIH application ID:** 9841366
- **Project number:** 5R03CA223717-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Jelena Todoric
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $78,750
- **Award type:** 5
- **Project period:** 2018-12-20 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841366

## Citation

> US National Institutes of Health, RePORTER application 9841366, Understanding the link between high-fructose intake and pancreatic cancer development (5R03CA223717-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9841366. Licensed CC0.

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