Low Oxygen Cellular Protein Synthesis Mechanism Discovered

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."

Comments

What percentage of cancers leverage that?

[Elgonn]

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.

Re:What percentage of cancers leverage that?

[Americano]

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.

Re:What percentage of cancers leverage that?

[ColdWetDog]

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.

Re:What percentage of cancers leverage that?

[ColdWetDog]

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.

Re:What percentage of cancers leverage that?

[Ungrounded Lightning]

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.)

Re:What percentage of cancers leverage that?

[dumcob]

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

Re:What percentage of cancers leverage that?

[nukeade]

Remarkably, not only is adaptation for low-oxygen conditions visible in the majority of malignancies (the Warburg Effect), but it's so prevalent it's actually considered one of the hallmarks of cancer. 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.

Re:What percentage of cancers leverage that?

[JMZero]

This kind of thinking is fantastically disconnected from reality - naive, junior-high, my-parents-don't-get-it thinking. Big pharma execs would do anything for a cancer cure; it would mean fame, money, and prestige out their eyes. And if one solitary idiot at that board meeting said something about not releasing it because of long term profits (or some other BS) he'd get laughed out of a job and be a funny story in someone's memoirs.

Now sure, they'd do what they could to milk it for profits - but they'd be damn sure it got out there before anyone else could. Hell, even if releasing it wasn't profitable at all (and it would be - obviously, obviously, obviously, obviously), they'd burn their company down if they had to.

Very, very few people would consider holding back on a cure for money; not many of those psychopaths have the personal skills to end up at the top of a big corporation, and getting a whole raft of them together would be nigh impossible. Imagining collusion across all the companies on something like this is ridiculous.

Re:What percentage of cancers leverage that?

[mopomi]

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 availability and is therefore essential in cellular oxygen homeostasis. This complex probably recruits functional homologues of the canonical eIF4E-dependent pathway, as well as distinct components, to initiate hypoxic protein synthesis. This process is regulated by the oxygen-sensing machinery first identified as the main regulator of the transcriptional response to hypoxia13, 14, 15, 16. A human population that recently migrated to the Tibetan highlands contains a point mutation in the gene encoding HIF-2α (EPAS1), further emphasizing the evolutionary role of HIF-2α in the adaptation to high altitude and low oxygen tension27. The target mRNAs code for proteins such as EGFR, PDGFRA and IGF1R that are implicated in the adaptive response to hypoxia as well as a wide variety of biological processes including development and cancer. The role of these receptor tyrosine kinases in human malignancy is particularly well documented and they are at the centre of targeted therapy11, 28. EGFR is often overproduced by tumours that harbour a wild-type EGFR gene, suggesting that cancer cells hijack the eIF4E2 pathway for their proliferative advantage29, 30. The results shown here provide the foundation for further investigation of the adaptive properties of the basic protein synthesis machinery in response to environmental conditions.

Re:What percentage of cancers leverage that?

[lisaparratt]

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.

Re:What percentage of cancers leverage that?

[Biotech_is_Godzilla]

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. 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...

Re:What percentage of cancers leverage that?

[sir-gold]

This kind of thinking is fantastically disconnected from reality - naive, junior-high, my-parents-don't-get-it thinking. Big pharma execs would do anything for a cancer cure; it would mean fame, money, and prestige out their eyes. And if one solitary idiot at that board meeting said something about not releasing it because of long term profits (or some other BS) he'd get laughed out of a job and be a funny story in someone's memoirs.

Now sure, they'd do what they could to milk it for profits - but they'd be damn sure it got out there before anyone else could. Hell, even if releasing it wasn't profitable at all (and it would be - obviously, obviously, obviously, obviously), they'd burn their company down if they had to.

Very, very few people would consider holding back on a cure for money; not many of those psychopaths have the personal skills to end up at the top of a big corporation, and getting a whole raft of them together would be nigh impossible. Imagining collusion across all the companies on something like this is ridiculous.

What exactly is a psychopath?

"Superficially charming, psychopaths tend to make a good first impression on others and often strike observers as remarkably normal. Yet they are self-centered, dishonest and undependable, and at times they engage in irresponsible behavior for no apparent reason other than the sheer fun of it. Largely devoid of guilt, empathy and love, they have casual and callous interpersonal and romantic relationships. Psychopaths routinely offer excuses for their reckless and often outrageous actions, placing blame on others instead. They rarely learn from their mistakes or benefit from negative feedback, and they have difficulty inhibiting their impulses."

Replace the word "fun" with "profit", and the word "romantic" with "economic", and you have the DEFINITION of any large publicly traded company

There has been at least one documentary showing that all corporations engage in psychopathic and sociopathic behaviors on a regular basis, especially in thier callous disregard for human life, the union carbide disaster is a great example of this.

if one solitary idiot at that board meeting said something about not releasing it because of long term profits (or some other BS) he'd get laughed out of a job

What if that "one solitary idiot" is the single largest shareholder (directly representing himself)? what are they going to do, laugh at him till he sells his share of the company? You assume that board members can be fired, but the majority of board members either personally own significant stock in the company, or they represent someone who does. The CEO (and CFO, CTO, etc) are the only ones who can be fired, because they are employees of the company, not shareholder representatives.

Give this guy a Nobel

[frank249]

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!

Re:Give this guy a Nobel

[Bengie]

Yeah, a poison trying to kill my-little-microbe-gut-friends(tm).

Re:filter based on user?

[similar_name]

I flag and report them. Don't know if it will help. I click the flag in the lower right. If anyone knows a better way...

Re:What's with the canadian flag?

[Kinky Bass Junk]

This is a science story about cancer. It's got nothing to do with Canada except for the fact that the researchers happen to be based there.

It's a Canadian story published in Canada about Canadian researcher. What did you expect, a US flag?

Re:What's with the canadian flag?

[mirix]

They usually have the 'Erlenmeyer flask and molecular stick-model' icon for science/research stories.

I wonder if that makes slashdot illegal in Texas?

(You need a permit to own a flask in Texas now. Apparently that's gonna slow the meth wildfire. What a joke).

Re:What's with the canadian flag?

[Samantha Wright]

Having been there, I can say conclusively that you have not answered the grandparent's second question. :)

Comment from the submitter

[_prime]

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 though interfering with the protein synthesis mechanism (as long as the patient is not at 10,000 feet) would result in some very good news for a lot of people. Like another commenter, I was hoping that someone in the audience who works in a related field could tell us if this would be effective for all or just some cancers. In any case, it sounds like a big step forward and I look forward to hearing more about it.

Re:What's with the canadian flag?

[mirix]

There's some info on texas department of public saftey's site

You need a permit to buy/possess:

(A) a condenser
(B) a distilling apparatus
(C) a vacuum drier
(D) a three-neck or distilling flask
(E) a tableting machine
(F) an encapsulating machine
(G) a filter, Buchner, or separatory funnel
(H) an Erlenmeyer, two-neck, or single-neck flask
(I) a round-bottom, Florence, thermometer, or filtering flask
(J) a Soxhlet extractor
(K) a transformer
(L) a flask heater
(M) a heating mantel or
(N) an adaptor tube

I didn't realise it was so broad. I suppose the condenser bit bans refrigeratiors and air-conditioning. 'Transformer' bans almost all electronics. Obviously it isn't enforced like this, but that's not really the point.

Apparently glassware (and chemistry in general) is only useful for making bombs and drugs, right?
Then they wonder why there is a shortage of scientists and engineers. It would be funnier if it wasn't so sad.

Re:So what's this mechanism.

[Samantha Wright]

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.

Re:So what's this mechanism.

[Samantha Wright]

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!