Study Shows how Chronic Inflammation Related to Alcohol Consumption Accelerates the Development of Pancreatic Cancer

A new study, published in the July issue of Cellular and Molecular Gastroenterology and Hepatology, suggests that inhibiting a cellular molecule called cyclic adenosine monophosphate (cAMP-) response element binding protein 1 (CREB) might thwart pancreatic tumor development in response to alcohol. CREB is a nuclear transcription factor known to be activated by multiple extracellular signals including growth factors and hormones. [1][2][3]

The study was supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) and the James Esther and King Biomedical Research Program of the Florida Department of Health. *

Researcher have found that despite the fact that CREB activates transcription of target genes in response to a diverse array of stimuli, including peptide hormones, growth factors, and neuronal activity, that activate a variety of protein kinases including protein kinase A (PKA), pp90 ribosomal S6 kinase (pp90RSK), and Ca2+/calmodulin-dependent protein kinases (CaMKs), the actual mechanism by which CREB activates transcription varies depending on the stimulus. [2] In some cases, signaling pathways target additional sites on CREB or proteins associated with CREB. This permits CREB to regulate distinct programs of gene expression under different and varying stimulating conditions. [2][3]

In normal, or healthy cells, CREB-activity is tightly regulated to ensure right response to extracellular cues at right time. However, CREB has been shown to be overactivated in multiple solid and liquid cancer tissues. Because CREB is import in normal physiology, it is important to understand the impact of pharmacological inhibition of CREB and to understand inhibition is is a viable strategy for developing novel anti-cancer therapeutics without deleterious effects in other organs.

As a result, the overactivation of CREB in cancer as well as CREB as a possible target for novel anti-cancer agent is being investigated.

Alcohol and cancer
Despite increasing evidence linking alcohol consumption to cancer, little is known about the biological mechanisms behind the association.

The new study suggests that inhibiting CREB might thwart pancreatic tumor development in response to alcohol. However, until recent, researchers did not understand the molecular interplay between oncogenic Kras ^G12D/+(Kras*) and CREB in promoting pancreatic cancer progression under chronic inflammation remains poorly understood.

“Our model serves as an important platform for understanding how chronic inflammation related to alcohol consumption accelerates the development of pancreatic cancer,” explained Siddharth Mehra, Ph.D., a scientist at Sylvester Comprehensive Cancer Center, and first author on the study.

Damaging impact
Chronic, high alcohol use damages acinar cells in the pancreas, specialized cells that produce digestive enzymes. The damage in turn causes the cells’ enzymes to increase inflammation in the tissue, exacerbating damage to the pancreas.

Over time, precancerous lesions can develop, increasing the risk for full-blown pancreatic cancer, one of the deadliest types of tumors. Previous studies have implicated CREB, a DNA-binding protein that regulates gene activity, and associated molecules in helping to mediate this process.

Progression to cancer also generally requires other cellular events, such as a mutation in a pro-cancerous gene called Ras, which commonly occurs in pancreatic tumors.

In the new study, the researchers developed a model that recapitulated alcohol-induced inflammation, the development of pre-cancerous lesions and progression to cancer. The model contained Ras mutations in acinar cells, and it also had an intact CREB gene that could be experimentally knocked out in these cells.

Alcohol-induced pancreatitis
The researchers found that exposure to alcohol and a pro-inflammatory molecule caused the development of symptoms similar to alcohol-induced pancreatitis, an inflammatory condition. Inflammation in turn prompted the development of precancerous lesions and, later, cancer. Consistent with previous studies, CREB was highly activated throughout this transition process.

The researchers next knocked out CREB and found that they could quell the development of precancerous and cancerous lesions, even in the continued presence of alcohol. Knocking out CREB also relieved damage to acinar cells.

The findings hint that inhibitors of CREB might have therapeutic potential in people who have high alcohol use. Such inhibitors could potentially relieve damage to the pancreas and thwart tumor development, said the researchers.

“We found that CREB is not just a mediator of inflammation; it is a molecular orchestrator that permanently converts acinar cells into precancerous cells, which ultimately progress to high-grade neoplasia,” said senior author Nagaraj Nagathihalli, Ph.D., associate professor of surgery and assistant director of the Sylvester Pancreatic Cancer Research Institute at the University of Miami.

More research needed
Future studies should help provide additional information about how alcohol use promotes pancreatic cancer development.

“Questions include whether similar events occur in human cells and tissues and what other molecules and cells play a role in the process. CREB activation may also be involved in other alcohol-linked cancers,” Nagathihalli speculated.

He and colleagues are also leveraging the model to investigate the potential of CREB inhibitors, which are under development as potential cancer therapeutics.

“We believe this study lays the groundwork for future translational efforts targeting CREB as a therapeutic vulnerability in inflammation-associated pancreatic cancer,” said study co-author Nipun Merchant, M.D., Sylvester associate director of translational science and chief of surgical oncology.
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Note: * The Histopathology Core Service was conducted with the assistance of the Sylvester Comprehensive Cancer Center support grant.
** The U.S. surgeon general recently declared alcohol the third leading preventable cause of cancer.

Reference
[1] Li BX, Gardner R, Xue C, Qian DZ, Xie F, Thomas G, Kazmierczak SC, Habecker BA, Xiao X. Systemic Inhibition of CREB is Well-tolerated in vivo. Sci Rep. 2016 Oct 3;6:34513. doi: 10.1038/srep34513. PMID: 27694829; PMCID: PMC5046085.
[2] Shaywitz AJ, Greenberg ME. CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem. 1999;68:821-61. doi: 10.1146/annurev.biochem.68.1.821. Erratum in: Annu Rev Biochem. 2003;72:vii. PMID: 10872467.
[3] Srinivasan S, Mehra S, Jinka S, Bianchi A, Singh S, Dosch AR, Amirian H, Krishnamoorthy V, De Castro Silva I, Patel M, Box EWI, Garrido V, Totiger TM, Zhou Z, Ban Y, Datta J, VanSaun M, Merchant N, Nagathihalli NS. CREB Drives Acinar to Ductal Cells Reprogramming and Promotes Pancreatic Cancer Progression in Preclinical Models of Alcoholic Pancreatitis. Cell Mol Gastroenterol Hepatol. 2025 Aug 12:101606. doi: 10.1016/j.jcmgh.2025.101606. Epub ahead of print. PMID: 40812683.

Featured image: Alcohol consumption. Photo Courtesy: © 2019 – 2025 Fotolia/Adobe. Used with permission.

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