Proline metabolism supports metastasis formation and could be inhibited to selectively target metastasizing cancer cells

Abstract

Metastases are the leading cause of mortality in patients with cancer. Metastasis formation requires cancer cells to adapt their cellular phenotype. However, how metabolism supports this adaptation of cancer cells is poorly defined. We use 2D versus 3D cultivation to induce a shift in the cellular phenotype of breast cancer cells. We discover that proline catabolism via proline dehydrogenase (Prodh) supports growth of breast cancer cells in 3D culture. Subsequently, we link proline catabolism to in vivo metastasis formation. In particular, we find that PRODH expression and proline catabolism is increased in metastases compared to primary breast cancers of patients and mice. Moreover, inhibiting Prodh is sufficient to impair formation of lung metastases in the orthotopic 4T1 and EMT6.5 mouse models, without adverse effects on healthy tissue and organ function. In conclusion, we discover that Prodh is a potential drug target for inhibiting metastasis formation.

Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization

“…Recent studies demonstrating the potential to selectively target metabolic dependencies of metastases show promise for safer therapeutic options. In one example, inhibition of PRODH, which is important in proline catabolism, efficiently suppressed lung metastases without any adverse effects on normal cells and organ function (Elia et al, 2017). In order to accommodate drastically different environments with different oxygen abundances, energy sources and nutrient availabilities, extreme metabolic flexibility is required.…”

Mechanisms of redox metabolism and cancer cell survival during extracellular matrix detachment

“…Furthermore, Prodh expression and proline catabolism is increased in metastases compared to primary breast cancers of patients and mice. Strikingly, antagonizing Prodh is sufficient to abrogate formation of lung metastases in two independent mouse models, without affecting healthy tissue or organ function (58). In aggregate, Prodh holds promise as a novel drug target to tip the balance of redox homeostasis in favor for blocking metastasis formation.…”

Structure, function, and mechanism of proline utilization A (PutA)

“…In this regard, elevated proline levels in Prodh −/− mice were found to inhibit glutamate decarboxylase, resulting in lower production of γ-aminobutyric acid (GABA) and lower GABA-ergic transmissions [8]. PRODH also has an important role in the metabolic changes associated with cancer [9–12]. Recently, down-regulation of PRODH, either by small molecule inhibition or knockdown, was shown to significantly reduce breast tumor cell growth in spheroid cultures and metastasis in mouse models of breast cancer [12].…”

“…PRODH also has an important role in the metabolic changes associated with cancer [9–12]. Recently, down-regulation of PRODH, either by small molecule inhibition or knockdown, was shown to significantly reduce breast tumor cell growth in spheroid cultures and metastasis in mouse models of breast cancer [12]. PRODH activity helps drive ATP synthesis due to coupling of proline oxidation with reduction of ubiquinone in the mitochondrial electron transport chain [12–14].…”

“…Recently, down-regulation of PRODH, either by small molecule inhibition or knockdown, was shown to significantly reduce breast tumor cell growth in spheroid cultures and metastasis in mouse models of breast cancer [12]. PRODH activity helps drive ATP synthesis due to coupling of proline oxidation with reduction of ubiquinone in the mitochondrial electron transport chain [12–14]. Proline catabolism also drives production of reactive oxygen species, which has been shown to induce apoptosis in mammal cells [9, 15, 16] and prolong life span of Caenorhabditis elegans [17].…”