Mitochondrial Metabolism in PDAC: From Better Knowledge to New Targeting Strategies

Abstract

Cancer cells reprogram their metabolism to meet bioenergetics and biosynthetic demands. The first observation of metabolic reprogramming in cancer cells was made a century ago (“Warburg effect” or aerobic glycolysis), leading to the classical view that cancer metabolism relies on a glycolytic phenotype. There is now accumulating evidence that most cancers also rely on mitochondria to satisfy their metabolic needs. Indeed, the current view of cancer metabolism places mitochondria as key actors in all facets of cancer progression. Importantly, mitochondrial metabolism has become a very promising target in cancer therapy, including for refractory cancers such as Pancreatic Ductal AdenoCarcinoma (PDAC). In particular, mitochondrial oxidative phosphorylation (OXPHOS) is an important target in cancer therapy. Other therapeutic strategies include the targeting of glutamine and fatty acids metabolism, as well as the inhibition of the TriCarboxylic Acid (TCA) cycle intermediates. A better knowledge of how pancreatic cancer cells regulate mitochondrial metabolism will allow the identification of metabolic vulnerabilities and thus novel and more efficient therapeutic options for the benefit of each patient.

Targeting Redox Metabolism in Pancreatic Cancer

“…This abundant stroma compresses the vasculature, which limits oxygen, nutrients, and drug delivery to the cells [ 17 , 18 ]. However, even if this stroma is a source of both physical and oxidative stress, PDAC cells are well adapted to such hostile conditions to reach their energetic and biosynthetic demands (i.e., by reprogramming their metabolism) [ 9 , 11 ].…”

“…In conclusion, the aggressive nature and specific features of PDAC justify the need to explore alternative and novel therapeutic approaches. In this context, the essential role of mitochondrial metabolism in pancreatic cancer has been demonstrated [ 10 , 11 , 24 , 25 , 26 , 27 , 28 ]. Therefore, targeting mitochondrial metabolism, in particular redox metabolism, is an attractive therapeutic option.…”

“…The knowledge of many features of metabolic reprogramming in PDAC did greatly increase during the past decade [ 5 , 6 , 7 , 8 , 9 ]. In particular, it is now known that mitochondrial metabolism is essential in PDAC as in other cancers, co-existing with aerobic glycolysis [ 10 , 11 ]. Mitochondria are multifunctional organelles involved in the balance between cell life and death.…”

“…Their main functions are the production of energy on the form of ATP by the respiratory chain in the inner membrane, the production of reactive oxygen species (ROS) also by the respiratory chain, and the intrinsic pathway of apoptosis. Their central role in the metabolism of carbohydrates, proteins and lipids is opening therapeutic options that we recently reviewed [ 11 ]. In the present review, we will focus on the role of mitochondria in ROS control, and on the approaches for targeting redox metabolism in PDAC.…”

4-Hydroxyphenylpyruvate Dioxygenase-Like Protein Promotes Pancreatic Cancer Cell Progression and Is Associated With Glutamine-Mediated Redox Balance

“…However there is accumulating evidence that mitochondria still affect tumor cells pleiotropically including anabolic process, redox balance, cell signaling, and cell death ( 15 ). As hubs for metabolic processes, mitochondria also play a significant role in PDAC ( 55 ). Additionally, with regard to PDAC’s association with mitochondrial dysfunction, extensive investigation of mitochondria-targeting chemotherapeutic drugs has been performed ( 14 ).…”