Increased mitochondrial proline metabolism
sustains proliferation and survival of
colorectal cancer cells
الباحث الأول:
Saif AL AQBI
الباحثين الآخرين:
Lynsey Burke1☯, Inna Guterman1
, Caleb Green1
, Kevin West3
,
Raquel Palacios-Gallego1
, Hong Cai1
, Constantinos Alexandrou1¤
, Ni Ni Moe Myint1
,
Emma Parrott1
, Lynne M. Howells1
, Jennifer A. Higgins1
, Donald J. L. JonesID1,4,
Rajinder Singh1,4, Robert G. Britton1
, Cristina TufarelliID1
, Anne Thomas1
,
Alessandro Rufin
المجلة:
PLOS ONE
تاريخ النشر:
None
مختصر البحث:
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 ar…
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.
