Cancer-Promoting Proteins Reveal Viable Target for Therapy
Madison, Wisconsin - Discovering how cells function at a molecular level is a little like playing with Legos without the directions and in the dark: You can’t see it and you don’t know exactly how all the pieces connect. So, shining a light on an important piece from time to time can make all the difference.
A University of Wisconsin-Madison research group recently was able to visualize a pair of proteins that are important to tumor initiation and metastasis. With their metaphorical flashlight in hand, researchers discovered exactly how these two proteins directly interact and lead to all sorts of cancerous behavior.
Using X-ray crystallography - a technique that reveals the arrangement of atoms by analyzing how x-rays diffracts through the crystals that have formed around a subject, in this case two proteins - researchers now understand where these two proteins link together. Knowing exactly how they connect gives researchers clues into how they can add their own building blocks to stop this dangerous interaction.
The proteins, MTDH (metadherin) and SND1 (Staphylococcal Nuclease Domain containing 1) are both found to be overexpressed in many types of cancer. MTDH was found to be important in tumor metastases and later found to be important for tumor initiation as well, so it seems to have effects at multiple stages in cancer development. SND1 is also an oncogene, meaning that if it is overexpressed, it is known to cause cancer.
“We knew that both proteins were found to be overexpressed in cancers, but now we know that the two proteins are working together,” said Yongna Xing, associate professor of oncology at the UW McArdle Laboratory for Cancer Research, the basic-research arm of the UW Carbone Cancer Center.
This MTDH/SND1 pairing is not specific to any one type of cancer, but instead is a more general mechanism across nearly all cancers. Breast cancer, the model used in this study, was used because it is a well-understood model.
Without ‘seeing’ the proteins, according to Xing, there was no clear way to determine where the single or multiple locations of MTDH and SND1 linked together. With the structure, she was able to directly test where
the interaction takes place. The study, published in Cell Report, was three years in the making.
The structure revealed two separate binding pockets that are important for the MTDH/SND1 interaction. “If you perturb a pocket, you potentially could reduce tumor development. That means we can use the structure to identify strategies to target this interaction which could reveal novel therapeutic agents,” said Xing.
MTDH is a long unstructured protein associated with SND1, a highly-conserved evolutionary protein important in microRNA function. Xing mapped the interaction motif and narrowed down the interaction range. Having the structure will inform future experiments in which Xing plans to make mutations in either MTDH or SND1 at the interface and see how crucial the interactions are for tumor promotion.
It’s not clear what exactly the mechanism of these two proteins is in tumor promotion, but the crystal structure also provides a platform for further study. According to Xing, the protein complex presumably recruits different signaling molecules, tumor-promoting proteins, and mediate other downstream signaling events that lead to tumor promotion, so she is excited about having this structure as a platform to better understand the signaling pathway.
With her preliminary work, Xing hopes her findings will warrant funding so she can continue this line of inquiry as a priority.
Date Published: 10/31/2014