If the right hand don’t get you, the left hand will

Do you know the source of the title?  I found it surprising.  Answer at the end.

Some cancer cells have elevated levels of an enzyme called PHosphoGlyceride DeHydrogenase (PHGDH, others have decreased levels.  Many cancers contain both types of cells.  Neither is good news.

Those cancers  with low levels of PHGDH  have slower growth.  That’s good news isn’t it?  No.  Such cells are more likely to metastasize.

Those with high levels of PHGDH are less likely to metastasize.  That’s good news isn’t it?  No. such cells grow faster.

So cancers with both types of cells are more aggressive.

Here’s how it works [ Nature vol. 605 pp. 617 – 617, 747 – 753 ’22 ].

PHGDH is on the pathway for synthesis of serine, an amino acid required for protein synthesis (like all of them).  So low levels of the enzyme result in less protein synthesis and less tumor growth.

So how is this bad?  PHGDH binds to another enzyme PFK (PhosphoFructoKinase) stabilizing it.  When PHGDH is low PFK enzyme levels are low, so the subsrate of PFK (fructose 6 phosphate) is diverted to making sialic acid, which modifies cell surface proteins making them more likely to migrate.

So blocking sialic acid synthesis reverses the effects of low PHGDH on cancer migration and metastasis — but it does potentiate cell proliferation.

You just can’t win

Things like this may explain other paradoxic and unexpected effects of enzyme blockade.

16 Tons by Tennessee Ernie Ford

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