Proline Metabolism in Tumor Growth and Metastatic Progression

Abstract

Cancer cells show a formidable capacity to survive under stringent conditions, to elude mechanisms of control, such as apoptosis, and to resist therapy. Cancer cells reprogram their metabolism to support uncontrolled proliferation and metastatic progression. Phenotypic and functional heterogeneity are hallmarks of cancer cells, which endow them with aggressiveness, metastatic capacity, and resistance to therapy. This heterogeneity is regulated by a variety of intrinsic and extrinsic stimuli including those from the tumor microenvironment. Increasing evidence points to a key role for the metabolism of non-essential amino acids in this complex scenario. Here we discuss the impact of proline metabolism in cancer development and progression, with particular emphasis on the enzymes involved in proline synthesis and catabolism, which are linked to pathways of energy, redox, and anaplerosis. In particular, we emphasize how proline availability influences collagen synthesis and maturation and the acquisition of cancer cell plasticity and heterogeneity. Specifically, we propose a model whereby proline availability generates a cycle based on collagen synthesis and degradation, which, in turn, influences the epigenetic landscape and tumor heterogeneity. Therapeutic strategies targeting this metabolic-epigenetic axis hold great promise for the treatment of metastatic cancers.

From Glucose to Lactate and Transiting Intermediates Through Mitochondria, Bypassing Pyruvate Kinase: Considerations for Cells Exhibiting Dimeric PKM2 or Otherwise Inhibited Kinase Activity

“…Arg, through either interconversion to metabolites as for proline catabolism or through citrulline/ornithine and the fumarate nucleotide cycle will also lead to pyruvate formation; however, this probably requires inter-organ communication and, thus, may not be found within a single cell. The crucial role of proline catabolism in tumor growth and metastatic progression is extensively reviewed in Phang (2019) and D'Aniello et al (2020).…”

Targeting the Proline–Glutamine–Asparagine–Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy

“…Many lines of evidence suggest that pro availability affects cancer growth and proliferation, supporting the strategies of targeting Pro-starvation development [ 129 ]. Two enzymes are particularly relevant: PYCR1 has been shown to play a positive role in supporting cancer cell survival [ 12 , 130 ], whereas ProDH/POX has been shown displaying pro-tumor or anti-tumor properties, depending upon the contexts of microenvironment and cancer type [ 4 ].…”

Membrane Transporters for Amino Acids as Players of Cancer Metabolic Rewiring

“…Given the scenario depicted above, it is not trivial to consider proline as a bridge between TCA and urea cycle with great relevance for cancer rewiring ( Figure 2 ). It is important to stress that in the context of cancer development, proline plays a unique role in tumor microenvironment influencing the remodeling of the extracellular matrix that is responsible for cancer aggressiveness and EMT [ 55 , 56 ].…”