Metabolic Alteration Bridging the Prediabetic State and Colorectal Cancer

Abstract

Prediabetes and colorectal cancer (CRC) represent compelling health burdens responsible for high mortality and morbidity rates, sharing several modifiable risk factors. It has been hypothesized that metabolic abnormalities linking prediabetes and CRC are hyperglycemia, hyperinsulinemia, and adipokines imbalance. The chronic stimulation related to these metabolic signatures can favor CRC onset and development, as well as negatively influence CRC prognosis. To date, the growing burden of prediabetes and CRC has generated a global interest in defining their epidemiological and molecular relationships. Therefore, a deeper knowledge of the metabolic impairment determinants is compelling to identify the pathological mechanisms promoting the onset of prediabetes and CRC. In this scenario, this review aims to provide a comprehensive overview on the metabolic alterations of prediabetes and CRC as well as an overview of recent preventive and therapeutic approaches for both diseases, focusing on the role of the metabolic state as a pivotal contributor to consider for the development of future preventive and therapeutic strategies.

SGLT2 inhibitor promotes mitochondrial dysfunction and ER-phagy in colorectal cancer cells

“…SGLT2 has been found significantly expressed in lung cancer metastasis, pancreatic and prostate adenocarcinomas, high-grade glioblastoma patients, cisplatin-resistant hepatoblastoma, renal cell carcinoma and its increased expression is related to a poor prognosis and decreased overall survival rates [ 3 – 7 ]. Particularly, high glucose levels can directly promote cancer onset and development with different mechanisms, including hyperinsulinemia, inflammation and adipokines imbalance, as well as providing cancer cells with important metabolic substrates [ 8 , 9 ]. In this scenario, the SGLT2 inhibitors (iSGLT2), canagliflozin, dapagliflozin, tofogliflozin and empagliflozin, have been increasingly studied, given their strong anti-hyperglycemic activity as well as their emerging anticancer effects [ 8 , 10 ].…”

“…As other iSGLT2, canagliflozin, besides the blood glucose decrease, has been described to have additional beneficial effects, such as reduction of atherosclerotic plaque formation and body weight in rodents and patients with or without type 2 diabetes [ 14 , 18 – 20 ]. Growing evidence, in vitro and in vivo, suggested the anticancer effects iSGLT2 canagliflozin, by impairing cell motility and survival as well as exerting cancer specific cytotoxicity alone and combined with oncological drugs [ 9 , 21 , 22 ]. Above all, iSGLT2 could reduce cancer cells glucose uptake and strongly impair cancer specific cell metabolism [ 9 , 23 ].…”

“…Growing evidence, in vitro and in vivo, suggested the anticancer effects iSGLT2 canagliflozin, by impairing cell motility and survival as well as exerting cancer specific cytotoxicity alone and combined with oncological drugs [ 9 , 21 , 22 ]. Above all, iSGLT2 could reduce cancer cells glucose uptake and strongly impair cancer specific cell metabolism [ 9 , 23 ]. Indeed, cancer cells adapt their metabolism to address the requirements of rapid growth, determining oncogenesis and metastasis [ 24 ].…”