Pancreatic most cancers, although uncommon, is without doubt one of the deadliest of cancers, killing practically 50,000 folks yearly and doing so shortly, primarily as a result of it metastasizes quickly via the physique. Barely one in 10 folks survive past 5 years.
However a discovery by chemists on the College of California, Berkeley, suggests a brand new strategy to sluggish or cease metastatic unfold of pancreatic and maybe different cancers.
In final week’s challenge of the journal Molecular Cell, Christopher Chang and his group at UC Berkeley, collaborating with Christine Chio’s group at Columbia College in New York, report that metastasis is triggered by the lack of an enzyme that repairs oxygen injury to proteins.
With out this enzyme to erase the oxidative injury, one specific protein in most cancers cells goes on to rev up power manufacturing and seed new cancers across the physique. The researchers confirmed this by pulling down ranges of the “eraser” enzyme in mice and in cultured mouse and human cells, or organoids. In each instances, this promoted the migration of most cancers cells and metastatic unfold.
The researchers are actually different cancers to see if this new kind of set off is widespread and are pursuing methods to spice up ranges of the enzyme to forestall the metastatic unfold of pancreatic most cancers cells.
“We’re really making an attempt to activate or increase an eraser, one thing that can reverse and produce you again to your regular state,” mentioned Chang, the Class of 1942 Chair within the Division of Chemistry and professor of molecular and cell biology. “That’s a really troublesome factor to do as a result of more often than not, when you concentrate on most cancers, you concentrate on inhibiting one thing that’s elevated within the illness.”
The eraser enzyme usually fixes oxidative injury — the addition of an oxygen atom — to 1 particular amino acid element of proteins: methionine. Proteins are chains of amino acids — there are 20 sorts in all — that naturally fold into shapes which are essential to their perform and exercise. Chemical modification of any of those amino acids can have an effect on each the form and performance of the protein, doubtlessly activating or inactivating it.
“That is the primary instance of a methionine oxidation occasion that instantly prompts protein perform to advertise cell migration,” mentioned Chio, an assistant professor of genetics and improvement at Columbia’s Herbert Irving Complete Most cancers Heart.
Redox switches in most cancers and ageing
The protein impacted by methionine oxidation is named pyruvate kinase M2 (PKM2). Chang’s group profiled pancreatic most cancers cells and located that oxidation of one of many many methionines on that protein triggered metastasis of pancreatic most cancers cells. Trying extra carefully, they discovered that oxidation of that single methionine allowed the PKM2 protein to latch onto three others similar to it to kind a tetramer that supercharged the exercise of energy-producing mitochondria within the most cancers cells, making them migrate and seed new cancers.
“These are like Lego blocks that come on and off,” Chang mentioned. “You possibly can have one protein, which is a monomer; it will possibly kind a dimer when two come collectively; after which two extra come collectively to make a tetramer. The tetramer is the strongest and most energetic, however often it’s reversible as a result of you’ll be able to erase that oxygen. However they’re principally glued collectively when you’ve that methionine single oxygen atom modification.”
In regular cells, oxidation of methionine to a methionine sulfoxide is reversed by an enzyme that removes the oxygen atom — that’s, reduces it. That enzyme, methionine sulfoxide reductase A (MSRA), seems to be suppressed in pancreatic most cancers cells, which permits oxidation to set off tetramer formation and increase respiration of most cancers cells and subsequent migration and metastasis. It didn’t, nonetheless, trigger the most cancers cells to develop.
“We discovered that the MSRA protein — what we name the eraser protein — naturally removes methionine sulfoxides and makes them again into methionines,” Chang mentioned. “However as pancreatic most cancers progresses, it will get down-regulated, and so that you principally lose your eraser to deliver all the things again to regular. These most cancers cells then enhance their mitochondrial respiration and oxidative phosphorylation. What the most cancers does is reprogram itself to continue to grow and rising.”
The invention of this oxidation-reduction, or redox, change in pancreatic most cancers means that comparable switches could exist in different cancers.
“Our work identifies MSRA, an eraser of methionine oxidation, as a novel tumor suppressor that impedes metastatic dissemination,” Chio mentioned. “By elucidating the elemental facets of MSRA perform in pancreatic most cancers, our findings lay the groundwork for redox-based focused therapies to suppress the metastatic development of pancreatic most cancers and doubtlessly different tumor sorts.”
Chang, who research how protein modifications, like oxidation, have an effect on their perform, famous that methionine and one other amino acid, cysteine, are distinctive in containing sulfur, which simply pairs with oxygen. Because of this, the physique wants particular enzymes to deoxygenate, or scale back, these two amino acids. Issues with these redox enzymes could also be widespread, as in ageing.
“Extra broadly, we’re trying to find different varieties of illnesses the place this single atom sign might additionally play a task,” he mentioned. “When you lose the eraser, you principally have a bunch of additional marks in your proteome which are type of written in ink, as an alternative of in pencil.”
The work was supported, partially, by the Nationwide Institutes of Well being (R01-GM139245, R01-CA240654). Different co-authors embody postdoctoral fellow Dan He, professor of chemistry Dean Toste and former doctoral scholar Alec Christian of UC Berkeley, and Huijin Feng, Belen Sundberg, Jiaxing Yang, Justin Powers, Richard Friedman and Michael Kluger of Columbia College.