Dogs, Cancer, Protein Folding and Your Computer

No. I haven’t abandoned this blog. I finally came up for air after literally eating and sleeping in the lab for over a month. Other than people at work and the takeaway/delivery guy I haven’t seen anyone outside that circle in several weeks. It’s possible that I’m still a little punchy from sleep deprivation and lack of social contact; this post might not make complete sense.

LLL12 inhibits STAT3 in Canine Osteosarcoma Cell Lines.

What???

Cell culture refers to the removal of animal or plant tissue and the growth of those cells in engineered conditions.  When a few cells of the primary culture are passaged into a new flask it becomes a cell line. Cancer cells, like the famous HeLa cell line, divide forever.

Sarcoma describes a group of cancers derived from mesenchymal cells; this means muscle, bone, cartilage, nerve, skin and connective tissue – this obviously includes osteosarcoma, bone cancer. 50% of dogs over the age of 10 will experience cancer and large breed dogs are at particular risk of osteosarcoma.

mesenchymal_home

Credit: AbD Serotec

STAT3 belongs to the STAT (signal transducer and activator of transcription) family of proteins and unlike many others (I’m looking at you pokeman), STATs do exactly what the name describes. STAT3 proteins relay signals from outside of the cell into the nucleus to activate transcription of DNA sequences – when needed.

STAT3pathway680

STAT3 signalling pathway. In this case LLL12 would take the place of the phosphate (blue circle) preventing activation and dimerization. Credit: SABioscience

One characteristic found in many cancer cells is the constitutive activation of STAT3 (i.e. they are always “on”); to add insult to injury the persistent activation of STAT3 also makes the cells more resistant to anti-cancer drugs. For these and a bunch of other reasons (anti-apoptotic activity, immune evasion, promotion of angiogenesis, etc.) STAT3 is considered a viable target for cancer treatment

LLL12 STAT3 space

STAT3 space filling model  Credit:  Neoplasia. 2010 January; 12(1):39-50

LLL12 is the name (IUPAC : 5-hydroxy-9,10-dioxo-9,10-dihydroanthracene-1-sulfonamide) of this molecule; the neat thing about it is that it was developed with the help of computer aided design to dock on the pTyr705 binding site. To put it in the modern parlance, STAT3 won’t be getting any action; it’s been phosphate-blocked.

Chemical formula of LLL12. Credit: Neoplasia

Chemical formula of LLL12.
Credit: Neoplasia. 2010 January; 12(1):39-50

Putting it all together a less esoteric title for the study could be:

The molecule named LLL12 obstructs the persistent activity of the STAT3 protein in dog bone cancer cells grown in vitro.

Not totally sure where I was going with the above but hopefully you learned a bit about cancer. I needed a story to that included dogs, protein conformation and computational assistance, cancer and chemistry to introduce the importance computers and to segue into how you can use your computer to advance research. That’s where distributed computing comes into the picture.

Distributed computing simply divides a complex problem into small computational problems and sends them to volunteers to perform those calculations while the computer is idle. The combined power of all those computers makes a virtual supercomputer.

As the above hopefully illustrates the importance of knowing a protein’s shape is of paramount importance when it comes to understanding it’s functions and interactions with other biomolecules. There are several projects that rely on volunteers to aid in our advancing of cancer, proteins most notably Rosetta@homeFolding@home and The Human Proteome Folding Project. And for those who don’t want to let the computer have all the fun there is Fold.It, a protein folding game.

Related links

Berkeley Open Infrastructure for Network Computing (BOINC) 

REFERENCE

Couto JI, Bear MD, Lin J, Pennel M, Kulp SK, Kisseberth WC, & London CA (2012). Biologic activity of the novel small molecule STAT3 inhibitor LLL12 against canine osteosarcoma cell lines. BMC veterinary research, 8 PMID: 23244668

Lin L, Hutzen B, Li PK, Ball S, Zuo M, DeAngelis S, Foust E, Sobo M, Friedman L, Bhasin D, Cen L, Li C, & Lin J (2010). A novel small molecule, LLL12, inhibits STAT3 phosphorylation and activities and exhibits potent growth-suppressive activity in human cancer cells. Neoplasia (New York, N.Y.), 12 (1), 39-50 PMID: 20072652

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