Featured Research

from universities, journals, and other organizations

Scientists tailor cell surface targeting system to hit organelle ZIP codes

Date:
April 17, 2012
Source:
University of Texas M. D. Anderson Cancer Center
Summary:
Scientists who developed a technology for identifying and targeting unique protein receptor ZIP codes on the cellular surface have found a way to penetrate the outer membrane and deliver engineered particles -- called iPhage -- to organelles inside the cell.

Scientists who developed a technology for identifying and targeting unique protein receptor ZIP Codes on the cellular surface have found a way to penetrate the outer membrane and deliver engineered particles -- called iPhage -- to organelles inside the cell.

In a paper recently published online in Nature Communications, the team led by researchers at The University of Texas MD Anderson Cancer Center reports packaging the phage particles with a peptide called penetratin to reach inside the cell.

This new capacity was used to screen for peptide ligands -- binding agents -- that connect to receptors on mitochondria, which generate a cell's energy, and ribosomes, which process mRNA to make proteins.

The team found a peptide that binds to a specific ribosomal protein called RPL29 which, when delivered with penetratin, disrupts ribosomal function and kills cells. Cell survival was reduced in both malignant and non-malignant cells and in both mouse and human cell lines.

"We provided proof-of-concept for a direct intracellular ligand-receptor screening technology, which is clearly an unmet need in cancer biology, along with the discovery of an organelle ZIP Code that mediates cell death," said Renata Pasqualini, Ph.D., co-senior author of the paper and a professor in MD Anderson's David H. Koch Center for Applied Research of Genitourinary Cancers.

The RPL29 pathway is a new cell death pathway. The researchers found evidence of three types of cell death caused by disrupting the pathway with the new ligand.

"The molecular tool reported here along with its future ramifications will hopefully be of interest to targeted drug development, gene delivery, and mechanisms of human organelle diseases," said Wadih Arap, M.D., Ph.D., also of the Koch Center.

The iPhage screens for ligands inside the cell

Arap and Pasqualini pioneered a screening technique that exploits the existence of unique ZIP Codes in the vascular system to identify molecular targets and the ligands that can be used to selectively hit them.

They developed engineered viral particles, called phage, and packaged them with massive peptide libraries. When injected, these phage/peptide combinations bind to specific receptors in the blood vessels and organs. Cells are then fractionated and analyzed to discover which ligands bind to specific surface proteins.

Arap, Pasqualini and their colleagues have a number of targeted drugs in various stages of development based on screening and then delivery with the combinatorial particles.

The team wondered whether packaging the particles with penetratin, which is known to cross membranes without requiring a cellular receptor, would allow their technology to work inside of cells. "Penetratin makes a little bubble on the cell surface and the bubble goes in through the membrane," Arap said.

They dubbed the combination of penetratin and phage particles "internalizing phage," or iPhage. In a series of experiments, the team found:

  • iPhage successfully entered normal and malignant cells in both mouse and human cell lines while the engineered phage alone, or phage packaged with mutated penetratin, did not gain entry.
  • Connecting iPhage with the mitochondria localization signal (MLS) peptide resulted in a 10-fold concentration of MLS-iPhage in mitochondria compared to simple iPhage, showing that specific organelles could be targeted.
  • To screen for new ligands that might target specific organelles, they attached a random peptide library to iPhage particles and treated the KS1767 cells. Subsequent analysis found the peptide that binds to RPL29.
  • Packaged with penetratin, this "internalizing homing peptide" with the ungainly name YKWYYRGAA killed 75 percent of cells in culture while the peptide alone or penetratin alone killed virtually none.
  • Signs of apoptotic, autophagic and necrotic cell death were found with electron microscopy in cells killed by the YKWYYRGAA-penetratin combination.

Future studies will be needed to understand the complex cell death mechanism caused by the combination.


Story Source:

The above story is based on materials provided by University of Texas M. D. Anderson Cancer Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. Roberto Rangel, Liliana Guzman-Rojas, Lucia G. le Roux, Fernanda I. Staquicini, Hitomi Hosoya, E. Magda Barbu, Michael G. Ozawa, Jing Nie, Kenneth Dunner Jr, Robert R. Langley, E. Helene Sage, Erkki Koivunen, Juri G. Gelovani, Roy R. Lobb, Richard L. Sidman, Renata Pasqualini, Wadih Arap. Combinatorial targeting and discovery of ligand-receptors in organelles of mammalian cells. Nature Communications, 2012; 3: 788 DOI: 10.1038/ncomms1773

Cite This Page:

University of Texas M. D. Anderson Cancer Center. "Scientists tailor cell surface targeting system to hit organelle ZIP codes." ScienceDaily. ScienceDaily, 17 April 2012. <www.sciencedaily.com/releases/2012/04/120417152742.htm>.
University of Texas M. D. Anderson Cancer Center. (2012, April 17). Scientists tailor cell surface targeting system to hit organelle ZIP codes. ScienceDaily. Retrieved July 28, 2014 from www.sciencedaily.com/releases/2012/04/120417152742.htm
University of Texas M. D. Anderson Cancer Center. "Scientists tailor cell surface targeting system to hit organelle ZIP codes." ScienceDaily. www.sciencedaily.com/releases/2012/04/120417152742.htm (accessed July 28, 2014).

Share This




More Plants & Animals News

Monday, July 28, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Traditional African Dishes Teach Healthy Eating

Traditional African Dishes Teach Healthy Eating

AP (July 28, 2014) Classes are being offered nationwide to encourage African Americans to learn about cooking fresh foods based on traditional African cuisine. The program is trying to combat obesity, heart disease and other ailments often linked to diet. (July 28) Video provided by AP
Powered by NewsLook.com
Asteroid's Timing Was 'Colossal Bad Luck' For The Dinosaurs

Asteroid's Timing Was 'Colossal Bad Luck' For The Dinosaurs

Newsy (July 28, 2014) The asteroid that killed the dinosaurs struck at the worst time for them. A new study says that if it hit earlier or later, they might've survived. Video provided by Newsy
Powered by NewsLook.com
Raw: Sea Turtle Hatchlings Emerge from Nest

Raw: Sea Turtle Hatchlings Emerge from Nest

AP (July 27, 2014) A live-streaming webcam catches loggerhead sea turtle hatchlings emerging from a nest in the Florida Keys. (July 27) Video provided by AP
Powered by NewsLook.com
Russia Saves Gecko Sex Satellite, Media Has Some Fun With It

Russia Saves Gecko Sex Satellite, Media Has Some Fun With It

Newsy (July 27, 2014) The satellite is back under ground control after a tense few days, but with a gecko sex experiment on board, the media just couldn't help themselves. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins