Increased mitochondrial proline metabolism sustains proliferation and survival of colorectal cancer cells

Abstract

Research into the metabolism of the non-essential amino acid (NEAA) proline in cancer has gained traction in recent years. The last step in the proline biosynthesis pathway is catalyzed by pyrroline-5-carboxylate reductase (PYCR) enzymes. There are three PYCR enzymes: mitochondrial PYCR1 and 2 and cytosolic PYCR3 encoded by separate genes. The expression of the PYCR1 gene is increased in numerous malignancies and correlates with poor prognosis. PYCR1 expression sustains cancer cells’ proliferation and survival and several mechanisms have been implicated to explain its oncogenic role. It has been suggested that the biosynthesis of proline is key to sustain protein synthesis, support mitochondrial function and nucleotide biosynthesis. However, the links between proline metabolism and cancer remain ill-defined and are likely to be tissue specific. Here we use a combination of human dataset, human tissue and mouse models to show that the expression levels of the proline biosynthesis enzymes are significantly increased during colorectal tumorigenesis. Functionally, the expression of mitochondrial PYCRs is necessary for cancer cells’ survival and proliferation. However, the phenotypic consequences of PYCRs depletion could not be rescued by external supplementation with either proline or nucleotides. Overall, our data suggest that, despite the mechanisms underlying the role of proline metabolism in colorectal tumorigenesis remain elusive, targeting the proline biosynthesis pathway is a suitable approach for the development of novel anti-cancer therapies.

Identification of functional gene modules by integrating multi-omics data and known molecular interactions

“…In Figure 4B , overexpression of COL10A1 enhances the proliferation, migration, and invasion of CRC cells ( Huang et al, 2018 ); MMP11 expression affects the immune response in CRC ( Buttacavoli et al, 2021 ); ADAM12 may play vital roles in the recruitment of immune cells in CRC ( Huang et al, 2021 ); and COMP promotes CRC cell proliferation partially through the activation of the PI3K/Akt/mTOR/p70S6K pathway ( Liu et al, 2018 ). In Figure 4C , ALDH4A1 deficiency leads to the accumulation of proline, which sustains the proliferation and survival of CRC cells ( Alaqbi et al, 2022 ), and MT3 plays a pivotal role in tumor formation, progression, and drug resistance ( Si and Lang, 2018 ). In Figure 4D , TRAK1 is a prognostic biomarker of CRC ( An et al, 2011 ).…”

Amino acid metabolism genes associated with immunotherapy responses and clinical prognosis of colorectal cancer

“…The catalysis of aldehyde dehydrogenase 4A1 (ALDH4A1) is the final step of both proline and hydroxyproline catabolism (Bogner et al, 2021). Therefore, the deficiency of ALDH4A1 could lead to the accumulation of proline, which sustains the proliferation and survival of colorectal cancer cells (Namavar et al, 2021;Alaqbi et al, 2022). FAS, the death receptor for FASL of cytotoxic T lymphocytes, plays a significant role in suppressing the progression and metastasis of colorectal cancer (Gu et al, 2020;Merting et al, 2022).…”

Functional Impact of a Cancer-Related Variant in Human Δ1-Pyrroline-5-Carboxylate Reductase 1

“…8 Another study by Ye et al on melanoma, a type of skin cancer, showed similar findings where an increase in PYCR1 expression correlated with increased melanoma cases. 11 PYCR1 has also been implicated in breast cancer, 12 melanoma, 7 multiple myeloma, 13 non-small lung cancer, 8 colorectal cancer, 14 for all of which a correlation between PYCR1 overexpression and metastatic growth has been shown. Despite the number of studies that have been published on the role of PYCR1 in cancer, to our knowledge, there have been no reports on specific PYCR1 variants that are found in cancer patients.…”

“… 8 Another study by Ye et al on melanoma, a type of skin cancer, showed similar findings where an increase in PYCR1 expression correlated with increased melanoma cases. 11 PYCR1 has also been implicated in breast cancer, 12 melanoma, 7 multiple myeloma, 13 non-small lung cancer, 8 and colorectal cancer, 14 for all of which a correlation between PYCR1 overexpression and metastatic growth has been shown.…”