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Canada Medicine News

Low Oxygen Cellular Protein Synthesis Mechanism Discovered 94

Posted by Unknown Lamer
from the live-forever dept.
New submitter _prime writes "Until recently the mechanism by which cells make proteins in low-oxygen environments has been unknown. As published in Nature (paywall) this week, the discovery of the mechanism by an Ottawa-based team of researchers potentially means it could be 'very easy to kill cancer cells' without harming normal cells because cancer cells leverage the same low-oxygen protein synthesis mechanism even in the presence of normal oxygen levels."
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Low Oxygen Cellular Protein Synthesis Mechanism Discovered

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  • by Elgonn (921934) on Monday May 07, 2012 @10:28PM (#39923289)
    Does someone know? The summary implies all of them. But considering cancer is more of a collection of problems rather than a specific issue it just seems unlikely.
    • by Americano (920576) on Monday May 07, 2012 @10:52PM (#39923441)

      Can't say definitively, but one of the major characteristics of cancer cells are that they evade apoptosis (cell 'suicide' in cases of damage, etc.), and if you go read up on apoptosis, you'll see that one of the common triggering effects is hypoxia (low oxygen). It's certainly conceivable that the cancer cells, in disregarding apoptosis commands, utilize this low-oxygen synthesis pathway to continue multiplying, and that preventing the cells from using that pathway would cause them to die normally - in other words, the cancer cell MAY receive the signal to die, and shut down its "normal oxygen" protein synthesis pathway, but start (or continue) using the low-oxygen pathway, instead of dying.

      Very speculative, but it could very well be something that's fundamental to many broad categories of cancer cell. IF it turns out to be as effective as suggested (hoped), it would add a powerful new treatment to the chemotherapy, radiation, and surgical treatments already being used. If it doesn't, it still offers some potential insight into how cancer cells function, which could lead to development of other treatment protocols. It could also lead to better treatments of heart disease & stroke, since lack of oxygen to various cells & organs is one of the major components of damage in both of those conditions.

      Wish Nature wasn't behind a paywall, the newspaper interview & writeup are interesting, but scant of detail.

      • by ColdWetDog (752185) on Monday May 07, 2012 @11:45PM (#39923725) Homepage

        Of note in the Nature article is that none of the breathless claims in the PR bit are even alluded to. The abstract (which is typically available):

        Protein synthesis involves the translation of ribonucleic acid information into proteins, the building blocks of life. The initial step of protein synthesis is the binding of the eukaryotic translation initiation factor 4E (eIF4E) to the 7-methylguanosine (m7-GpppG) 5cap of messenger RNAs1, 2. Low oxygen tension (hypoxia) represses cap-mediated translation by sequestering eIF4E through mammalian target of rapamycin (mTOR)-dependent mechanisms3, 4, 5, 6. Although the internal ribosome entry site is an alternative translation initiation mechanism, this pathway alone cannot account for the translational capacity of hypoxic cells7, 8. This raises a fundamental question in biology as to how proteins are synthesized in periods of oxygen scarcity and eIF4E inhibition9. Here we describe an oxygen-regulated translation initiation complex that mediates selective cap-dependent protein synthesis. We show that hypoxia stimulates the formation of a complex that includes the oxygen-regulated hypoxia-inducible factor 2 (HIF-2), the RNA-binding protein RBM4 and the cap-binding eIF4E2, an eIF4E homologue. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP)10 analysis identified an RNA hypoxia response element (rHRE) that recruits this complex to a wide array of mRNAs, including that encoding the epidermal growth factor receptor. Once assembled at the rHRE, the HIF-2–RBM4–eIF4E2 complex captures the 5cap and targets mRNAs to polysomes for active translation, thereby evading hypoxia-induced repression of protein synthesis. These findings demonstrate that cells have evolved a program by which oxygen tension switches the basic translation initiation machinery.

        Is certainly consistent with your thoughts on apoptosis but there is scant discussion in TFA.

        • by mopomi (696055)
          You can usually get past a paywall by going to your local public or university library and accessing the article there. Tedious, I know.
          Conclusions from the article:

          Here we have identified a selective cap-dependent translation initiation mechanism that operates independently of eIF4E and that targets mRNAs for protein synthesis during hypoxia. The results suggest that the HIF-2αâ"RBM4â"eIF4E2 complex is extensively involved in coordinating the translation response to low oxygen avail

      • by nukeade (583009) <serpent11.hotmail@com> on Tuesday May 08, 2012 @12:21AM (#39923921) Homepage

        Remarkably, not only is adaptation for low-oxygen conditions visible in the majority of malignancies (the Warburg Effect [wikipedia.org]), but it's so prevalent it's actually considered one of the hallmarks of cancer [wikipedia.org]. The reason this happens is easy to imagine: since the tumor has an extreme growth rate and abnormal vasculature, it may have trouble getting the amount of oxygen tha cells normally need in order to survive. It's likely that if they can actually safely target this pathway, they may have the next blockbuster cancer drug on their hands.

        • by Biotech_is_Godzilla (2634385) on Tuesday May 08, 2012 @06:58AM (#39925663)

          Mod parent up. I just signed up for an account to say exactly the same thing.

          To add to this, the major thing about Warburg metabolism is that not only does it allow cancer cells to survive in low-oxygen conditions; it actually produces the raw materials for making the protein needed to grow new cancer cells, so it allows cancer cells to grow faster than if they were using normal aerobic respiration. Here's James Watson talking about it in the NYT [nytimes.com]. So the low-oxygen conditions in a tumour are an evolutionary selection pressure for tumours to evolve towards dealing with low-oxygen conditions, but probably also for them to evolve towards growing faster and being more malignant too.

          In the study in the OP they already knew the normal gubbins that engages the services of the protein-making machinery doesn't work in low-oxygen conditions, so they went looking for something that does work under these conditions and found it. It normally exists in cells so that they can make proteins when starved of oxygen. What's not clear from the Nature abstract, and what will probably need more work to study, is whether this pathway is massively boosted in cancer cells. My guess is that it will be. The Warburg effect is interesting and unique to cancer cells, but it's difficult to turn into a treatment as it's a perversion of a pathway that's essential in all cells - if you drug the pathway itself you'll likely kill the patient. This study is different as it's a pathway that's specific to oxygen-starved cells, so it may well (in about 20 years) provide some exciting new 'universal' drug targets for solid tumours, that may not kill them dead but might at least slow them down. Don't take up smoking yet though...

    • by ColdWetDog (752185) on Monday May 07, 2012 @10:55PM (#39923461) Homepage

      Interestingly the Nature article doesn't make mention of this mechanism in cancer cells other than to show it exists in a particular brain cancer clone. As the saying goes, 'extraordinary claims require extraordinary data' - at this point we're at the mercy of the idiot PR summary and a single statement from one of the researchers.

      The idea that you could wipe out cancer cells selectively (if this pathway is indeed common to malignant cells AND not required by normal cells) is nice but lets hold our breath, shall we.

      I've lost count on how many times cancer has been cured according to various and sundry press releases. Of interest perhaps, is that there isn't an editorial note on the paper. Nature tends to do this for papers that they perceive to have a major result. The editorial typically gives some background and insight to the paper to allow people who aren't in the field to understand it's significance.

      • by Ungrounded Lightning (62228) on Monday May 07, 2012 @11:48PM (#39923741) Journal

        One of the main problems cancer cells have is getting enough oxygen.

        Their continuous unregulated reproduction outgrows their blood supply - and while a typical tumor signals for more blood vessel growth (vascularization) into itself, the vessels themselves are organized so they can't really keep up. The result is that the bulk of a solid tumor is running on very low oxygen concentration, the main limit on its growth is its ability to obtain new vascularization, and a substantial fraction of the cancer cells may be dying off due to this oxygen shortage.

        So of course having essentially every low-oxygen hack available turned on is a reasonable thing to expect of dangerous tumor types. And turning them off, even through it might not completely kill the tumor, would knock it down enormously AND the remainder would be expected to be far more vulnerable to the body's immune system.

        (Of course if the tumor is a type that recognizes it should die but is evading apoptosis because that works on the normal but not the low-oxygen pathway, turning off the low-oxygen pathway means the cancer cells should just commit suicide, either completely killing the tumor or knocking it back to a miniscule number of cells with further mutations.)

        • by dumcob (2595259)
          Very well explained. Here is a nice animation (which is very similar to what you just described) of how the drug Avastin works. It essentially interferes with the "signal" for new blood vessel growth. Is already in use along with chemo for many cancer treatments.

          http://www.youtube.com/watch?v=3xmlYr1AGx8 [youtube.com]
          • Wow, watching that movie, it's incredible how complex a tumor can be. The tumor releases VEGF-A to stimulate blood-vessels to grow around it, so it can get the blood flow needed to power itself. It's almost as if cancer is a parasite that has evolved to complexly interact with the human body.....
            • Cancer *is* the human body, gone rogue and psychopathic. It's got all your superpowers, knows all your secrets, and is damned well going to use them to it's own benefit, the rest of you be damned.

            • There was a paper about a year or so ago that posited that cancer was actually a different strategy for multicellular life, a default state of being that more structured organisms evolved from by taming it and poking with developmental genes to direct what happens. I believe the notion came out of analysing fossils of the earliest known (and definitely unstructured) multicellular life and deciding that the organisation in it resembled a tumour. It's funny—we name so many oncogenes tumour suppressors b

      • by Belial6 (794905)
        I've lost count too, but what I can count are the people I have personally known who have died of cancer, and those that have been cured. The cured out number the dead at least 5 to 1.
    • There's probably not a list, given how many kinds of cancer there are, and the difficulty of determining biological mechanisms. Cancers are diverse, but there are certain things that most of them do, and that's where therapies are developed. A big one is overexpression of receptors or antibodies, which not all cancers do in the same way, but most do in some fashion. I'd imagine anything that kills most cancers without killing healthy cells is worth a go.

      But that's a double edged sword. I was more surprised
  • by frank249 (100528) on Monday May 07, 2012 @10:32PM (#39923309)

    This has the potential to replace chemo therapies with an antibiotic. No more poisoning people to try to make them better. Not to mention the potential to treat stokes and heart disease. Well done!

    • This has the potential to replace chemo therapies with an antibiotic. No more poisoning people to try to make them better. Not to mention the potential to treat stokes and heart disease. Well done!

      First, they only hand out Nobels to famous people these days, not people who should be famous because of their work. Al Gore won one for giving a powerpoint about Global Warming... the hundred plus scientists who have dedicated their lives to collecting, analyzing, and releasing the data haven't gotten anything. I can provide many more examples of how much fail there is in the Nobel prize world... Winning one is no longer any great achievement... you can just buy one these days.

      Second.. it's a bit early to

      • by ltcdata (626981)

        This has the potential to replace chemo therapies with an antibiotic. No more poisoning people to try to make them better. Not to mention the potential to treat stokes and heart disease. Well done!

        First, they only hand out Nobels to famous people these days, not people who should be famous because of their work. Al Gore won one for giving a powerpoint about Global Warming... the hundred plus scientists who have dedicated their lives to collecting, analyzing, and releasing the data haven't gotten anything. I can provide many more examples of how much fail there is in the Nobel prize world... Winning one is no longer any great achievement... you can just buy one these days.

        Second.. it's a bit early to congratulate them... they've published a paper, not cured a patient.

        obama and the nobel price for peace...

        • by ltcdata (626981)
          priZe... sorry... its the same as the word value "precio" in my language, spanish, i had a brainfart and wrote "price".
          • ? premio = precio?
            • by ltcdata (626981)
              when you speak it, its has a similar phonetic signature, when i speak "prize" y think of "precio, (value, cost) so without thinking, i wrote "price".
              • Must be tough having a language barrier in your own head. /jk
                • by ltcdata (626981)
                  when you work and constantly switch languages, read in english, then spanish, then english.... things like this happens.
              • by X0563511 (793323)

                They do? I thought, in Spanish, that you speak that "M" with your lips (as in English) and the "C" with your tongue (like a shortened S). Totally different sound structure.

                Not that I speak Spanish, so please correct me :)

                • by ltcdata (626981)
                  What you say about pronunciation is true. "Prize" in spanish is prononunced something like "prais". The sound of the spoken word "Precio" is kind of similar to "price" and "prize" in spanish, that's why i got confused when i wrote it.
      • by glwtta (532858)
        Last year's Nobel in Physiology and Medicine went to the discoverers of the Toll gene and Toll-like receptors (as well as dendritic cells), which play a major role in immune response activation.

        You're right, what a fucking joke.
      • Al Gore won one for giving a powerpoint about Global Warming... the hundred plus scientists who have dedicated their lives to collecting, analyzing, and releasing the data haven't gotten anything.

        Your talking about the 'peace prize' which is has always been contraversial, even more so when people don't bother to check the facts. Gore was jointly awarded the peace prize [nobelprize.org] along with the thousands of scientists who have also DONATED their time to the IPCC reports over the last couple of decades. Gore is not a member of the IPCC but his 'slide show' put AGW into the venacular of the US public, so much so that many Americans still think it didn't exists before Gore started banging on about it in movie the

    • by Eukariote (881204)
      Too late. It has already been awarded in 1931 [hopeforcancer.com] . Yes, the import of anearobic metabolism on cancer emergence has been known of for over 80 years. Indeed, Dr. Johanna Budwig [healingcan...urally.com] has developed an effective dietary treatment based on it. She was nominated for a Nobel seven times, but never awarded one.
      • by sFurbo (1361249)
        The lists of Nobel nominees are not publically available. Claiming someone has been nominated a certain number of times is clearly a falsehood.

        Now, what does WP says of this treatment? "Evidence for the effectiveness of the Budwig diet is limited as most research has only been done on cell culture studies and experiments on rats and mice with inconsistent results.[...] There is no reliable evidence available for the effectiveness of the full Budwig protocol."
        That doesn't really sound like Nobel material
        • by Eukariote (881204)

          The lists of Nobel nominees are not publically available. Claiming someone has been nominated a certain number of times is clearly a falsehood.

          Nonsense. Those who nominated a peer for a Nobel can and have given publicity to their actions, particularly when they felt him or her to have been unjustly denied the award.

          In contrast to the sweeping unsubstantiated WP quote you offer, there is plenty of reliable evidence for the effectiveness of the Budwig protocol: it moved out of the research stage decades ago a

          • by sFurbo (1361249)

            A good place to start are the words to two-time Nobel prize winner Linus Pauling: "Everyone should know that the 'war on cancer' is largely a fraud."

            I was going to write a longer answer, but then you quoted Linus Pauling on cancer treatment. His view on that subject is the poster example of why you shouldn't rely on the words of a Nobel laureate on anything out of their main field, if that. Quoting him for wisdom on cancer treatment shows you don't know the first thing of the subject. Of course, even if you hadn't done that, your suggestion that testimonials is a good way to tell whether a treatment works shows that.

            • by lxs (131946)

              Pauling won not one but two Nobel prizes and went quite kooky in his old age, he also reached his 90s with a cancer that should have killed him when he was in his 60s. He may have been lucky or he may have been on to something.

              • by sFurbo (1361249)
                No, we have tested it, he was just lucky, or at least, it doesn't seem to work for any subgroup of patients we can identify. He was not on to a universal cure for cancer.
            • A good place to start are the words to two-time Nobel prize winner Linus Pauling: "Everyone should know that the 'war on cancer' is largely a fraud."

              Ah, the good old "appeal to authority". Always a sign that someone's talking out of the wrong orifice.

  • It's a pity that the non-paywall article doesn't say SQUAT about what the mechanism ACTUALLY IS.

    (I wonder if that's deliberate, to get more people to pay up.)

    • It's actually described rather well in the abstract of the journal article. What level of detail were you hoping for? I might be able to quench your curiosity.
      • What level of detail were you hoping for? I might be able to quench your curiosity.

        Probably not; to be blunt, people who post comments like GPP's are more interested in whining than they are in knowledge.

        • by Samantha Wright (1324923) on Tuesday May 08, 2012 @05:19AM (#39925293) Homepage Journal

          I did think about making the (extremely obvious) remark that if one is capable of handling that question, one already has access to Nature and is well-acquainted with why there's a "paywall", and why the Ottawa Citizen is not even remotely the appropriate venue for discussing hypoxia pathways or translation initiation factors—but that does look slightly worse on one's permanent record, and it burns up the opportunity for someone else to come along and have the question answered in a more serious light.

          And to be honest, Slashdot doesn't need more snarkery. One of its greatest assets is its plenitude of technically intelligent and experienced comment-posters, and that's a really wonderful resource for a community to have. Cynicism can do little but poison the site's ability to attract new users—and there have been lots of times I wish I could hit someone on the head (often myself) for unnecessary posturing, taking up a position of authority obviously beyond the extent of his or her knowledge, or responding to sloppy critique with an outright attack. Being unexpectedly kind can get jerkwads to shut up, too—and it's more likely to make the impressionable newbie or lurker contribute positively in the future, rather than emulating (limp-wristedly) the venom of others.

          • I admire your optimism. And that's not snark; I really do. For myself, I do my best to answer what I perceive to be honest questions, but there is just so damned much wilful ignorance on display in any science-related story that I often have a hard time keeping my baser instincts in check.

            • Well... there's the trick. That's when keeping up a strong face is the most important. I really feel like Slashdot is considered a sanitized version of 4chan these days as far as social forums go: poisonous, but not miserable enough to descend to the point that clever and ridiculous trolls are its life's blood. If the staff cared about anything long-term I have a feeling more care would've been taken. There was a time when the site was ranked higher than #1,734 by Alexa!
  • To me the Canada flag thing has become a tongue-in-cheek posting icon. The system auto-selects it depending on the keywords entered by the submitter. Given the Canadian article and research team I thought the tag was appropriate, but I have to chuckle when the flag appears (though I suppose it does help us canucks with USA inferiority complex feel a bit better - how many flags can we get up here guys!).

    Bottom line: this sounded like something people need to know about. The way the article reads it seems as

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