Type 1 and type 2 diabetes confer an excess pancreatic cancer (PaC) risk of similar magnitude, suggesting a common mechanism. We have shown that Advanced glycation end-products (AGEs), the levels of which are increased in both types of diabetes, promote PaC growth and that the L-carnosine derivative FL-926-16 is highly effective in preventing the PaC-promoting effect of diabetes by counteracting carbonyl stress. This project is aimed at i) demonstrating that glucose-related reactive carbonyl species (RCS) and their protein adducts (i.e., AGEs) induce the activation of YAP, a downstream target of KRAS signalling, and ii) validating a molecular mechanism implicating carbonyl stress-mediated YAP induction through decrease of the tumor suppressor LATS1, a negative regulator of YAP, and increase of EGFR phosphorylation, a known YAP activating factor. These objectives will be pursued by investigating:
1. the role of RCS and AGEs (i.e., carbonyl stress) as mediators of the proliferation-promoting effect of high glucose (HG) through activation of a LATS1/EGFR/YAP pathway in human pancreatic ductal adenocarcinoma (PDA) cells;
2. the protective effects of the RCS-sequestering and AGE inhibitor compound FL-926-16 on glucose-, RCS- and AGE-induced proliferation and YAP activition in PDA cells;
3. the effects of diabetes and FL-926-16 on the levels of AGEs and YAP activity in PaC specimens from the Pdx1-Cre;LSL-KrasG12D/+ (KC) mouse model;
4. the association between AGEs and nuclear YAP levels in human pancreatic adenocarcinoma tissues;
5. the effects of serum from diabetic patients on proliferation and activation of a LATS1/EGFR/YAP axis in PDA cells.
Overall, this study will clarify the mechanisms underlying the diabetes-cancer link and will provide evidence that carnosine derivatives represent a promising class of RCS-scavenging agents useful not only in metabolic disorders, but also in risk management and prevention of cancer, particularly in high-risk diabetic patients.
Although the link between oxidative stress, cancer development, progression and response to therapy is clearly established, carbonyl stress and cancer connection remains largely unexplored and
has never been envisaged as potentially interconnected. To the best of our knowledge, only two studies have reported RCS-derived AGEs detection in malignant tumors [1,2]. What is more, despite epidemiological evidence demonstrating increased PaC risk with both types 1 and 2 diabetes [3-5], the mechanisms underlying the cancer-promoting effect of diabetes still remain to be elucidated.
This study follows-up our previous findings [6] demonstrating that FL-926-16 is highly effective in preventing the PaC-promoting effect of diabetes in a mouse model of Kras-driven PaC by counteracting carbonyl stress and AGE accumulation in tumor tissue and plasma. These findings are the result of a successful use of Progetti di Ateneo Funds (Progetto di Ateneo 2018).
By using in vitro human pancreatic adenocarcinoma (PDA) cell lines and ex vivo tissues (plasma and pancreatic tumor specimens) from both mice and humans, this study will provide evidence of the involvement of an RCS/AGE-YAP pathway in the association between diabetes and PaC risk. On the whole, our study has been designed to unravel the molecular mechanism(s) underlying the diabetes-cancer link and to provide evidence that carnosinase-resistant carnosine derivatives represent a promising class of RCS-scavenging agents useful not only in the treatment of metabolic disorders [7,8], but also in risk management and prevention of cancer, particularly in high-risk diabetic patients.
References
1. Nokin MJ et al Elife 2016, 5. pii: e19375
2. van Heijst JW et al, Cancer Letters 2006, 241:309-319
3. Ben Q et al Eur J Cancer 2011;47:248-254
4. Li D et al Cancer Causes Control 2011;22:189-197
5. Carstensen B et al Diabetologia 2016;59:980-988
6. Menini S, Iacobini C, Pugliese G et al. Diabetes-associated carbonyl stress promotes pancreatic cancer growth: evidence for a protective role of the carbonyl-sequestering agent FL-926-16. Manuscript in preparation for submission
7. Anderson EJ et al J Clin Invest 2018;128:5280-5293
8. Haus JM, Thyfault JP. J Clin Invest 2018;128:5198-5200