Effect of Proton Pump Inhibitors on Colorectal Cancer

Abstract

Proton pump inhibitors (PPIs) are administered commonly to aged people; however, their effect on colorectal cancer (CRC) has still not been fully elucidated. Here, we examined the effect of PPIs and consequent alkalization on CRC cells. PPI administration alkalized the fecal pH and increased serum gastrin concentration. PPI and pH8 treatment (alkalization) of CMT93 mouse colon cancer cells inhibited cell growth and invasion, increased oxidative stress and apoptosis, and decreased mitochondrial volume and protein levels of cyclin D1 and phosphorylated extracellular signal-regulated kinase (pERK) 1/2. In contrast, gastrin treatment enhanced growth and invasion, decreased oxidative stress and apoptosis, and increased mitochondrial volume and cyclin D1 and pERK1/2 levels. Concurrent treatment with a PPI, pH8, and gastrin increased aldehyde dehydrogenase activity and also enhanced liver metastasis in the BALB/c strain of mice. PPI administration was associated with Clostridium perfringens enterotoxin (CPE) in CRC lesions. CPE treatment activated yes-associated protein (YAP) signals to enhance proliferation and stemness. The orthotopic colon cancer model of CMT93 cells with long-term PPI administration showed enhanced tumor growth and liver metastasis due to gastrin and YAP activation, as indicated by gastrin receptor knockdown and treatment with a YAP inhibitor. These findings suggest that PPI promotes CRC growth and metastasis by increasing gastrin concentration and YAP activation, resulting in gut flora alteration and fecal alkalization. These findings suggest that PPI use in colorectal cancer patients might create a risk of cancer promotion.

Proton Pump Inhibitors and Cancer Risk

“…[43][44][45][46][47] In addition, long-term use of PPIs was suggested to significantly alter the abundance and microbial diversity of gastrointestinal symbiotic bacteria and to promote activation of related proteins or production of carcinogenic substances, which was also associated with the development of related cancers. 16,48,49 Specifically, in pancreatic cancer, prolonged acid-suppression may promote nitrate-reducing bacteria to produce potential carcinogenic N-nitroso compounds, which would cause further pancreatic damage and even pancreatic cancer. 50 As for colorectal cancer, it was demonstrated that PPIs administration would promote growth of Clostridium perfringens and induce significant release of their enterotoxin to stimulate the progression of colorectal cancer by activating yes-associated protein.…”

Colorectal cancer treatment using bacteria: focus on molecular mechanisms

“…This complex is known as a “multi-protein membrane pore complex” and causes the lysis of cancerous cells through losing cellular osmotic equilibrium. The anti-cancer feature of CEP for CRC cells was confirmed in in vivo and in vitro studies [ 46 , 47 ]. For instance, Pahle et al , (2017) verified an optimized CPE expressing vector as a target for claudin-3 and/or claudin-4 expressing in colon cancer cells including SW-480, HCT-116, SW620, Caco-2, HT-29 and PDX (patient-derived colon carcinoma xenografts).…”

Proton pump inhibitors and sensitization of cancer cells to radiation therapy

“…Notably, patients on PPIs showed decreased levels of cyclin D1 (35). Additional studies found that the expression of cyclin D1 is significantly reduced in pancreatic and colorectal cancer cells treated with PPIs (36). Given their FDA-approval, the pleiotropic effect of PPIs to maintain the expression of Bax and to decrease cyclin D1 levels may be an attractive strategy to overcome the resistance of cancer cells to radiation therapy.…”