Navigation Links
An Achilles heel in cancer cells
Date:12/8/2008

A protein that shields tumor cells from cell death and exerts resistance to chemotherapy has an Achilles heel, a vulnerability that can be exploited to target and kill the very tumor cells it usually protects, researchers from the University of Illinois at Chicago show in a new study published in the Dec. 9 issue of Cancer Cell.

Akt is a signaling protein, called a kinase, that is hyperactive in the majority of human cancers.

"Akt is perhaps the most frequently activated oncoprotein (cancer-promoting protein) in human cancer," says Nissim Hay, professor of biochemistry and molecular genetics at the UIC College of Medicine. Pharmaceutical companies have been trying to find ways to inhibit Akt to improve cancer therapy, he said, but most candidate drugs have acted too broadly and proved toxic.

"One of Akt's major functions in tumor cells is promoting cell survival," Hay said. "Tumor cells with hyperactive Akt are not only resistant to the external stresses that can induce cell death but also to chemotherapy."

But Akt is also required for metabolism and the proliferation of cancer cells, and it was as a byproduct of its role in metabolism that the researchers were able to exploit Akt hyperactivity against the tumor cell.

"We found that cells with hyperactive Akt have increased intracellular levels of reactive oxygen species (ROS) and at the same time impaired ability to scavenge ROS," Hay said. These ROS are highly reactive byproducts of metabolism that can damage the cell. Cells usually respond to high levels of ROS by undergoing cell suicide, or apoptosis.

"And, to our surprise, we found that although Akt can protect cancer cells from many of the external signals that would ordinarily induce cell death, including many chemotherapy drugs, it cannot protect from ROS inducers," said Hay.

The researchers found that if they treated cancer cells with chemicals that raise ROS levels, the cells die. Akt could not protect cells from this form of apoptosis and, indeed, because Akt impaired the normal ROS scavenging in the cell, hyperactive Akt actually had the effect of making the cells more vulnerable to these ROS inducers. This enabled selective killing of cancer cells, expressing hyperactive Akt, and not normal cells.

The researchers also devised another strategy to exploit Akt's Achilles heel to successfully target and kill cancer cells.

An FDA-approved chemotherapy drug called rapamycin can be used to arrest cell tumor growth. A drawback of this drug is that it doesn't kill the cells, it just arrests the growth of the tumor. When the drug is removed the tumor may grow again.

"Rapamycin's other drawback is complicated feedback regulation that we turn to our advantage," Hay said. "It turns out rapamycin's target and Akt talk to each other in the cell." If the rapamycin target is hyperactive, Akt is inhibited, and if Akt is active, the rapamycin target is activated.

"So even though cancer cells treated with rapamycin stop dividing, they activate Akt, which makes the cells more resistant to other chemotherapy drugs," said Hay. "But we use that to our advantage. Because overactivation of Akt sensitizes the cells to ROS mediated cell death, if we treat the cells with ROS inducers and rapamycin together we can now kill the cells, not just arrest their growth."

The new study "provides a proof of the principle that Akt's Achilles heel -- a consequence of its role in metabolism -- can be exploited in at least these two ways to selectively target and kill cancer cells," Hay said.


'/>"/>

Contact: Jeanne Galatzer-Levy
jgala@uic.edu
312-996-1583
University of Illinois at Chicago
Source:Eurekalert

Related medicine news :

1. Ultrasound-guided injections help ease chronic Achilles tendon pain
2. Uncovering the Achilles heel of the HIV-1 envelope
3. Findings point to molecular Achilles heel for half of breast cancer tumors
4. Achilles Tendon Surgery Advances Speed Recovery
5. Scientists see Norwalk virus Achilles heel
6. Conventional prognostic factors fail to explain better prostate cancer survival in most Asian men
7. Survival differences by race most apparent in advanced stages of breast cancer
8. MRI finds breast cancer before it becomes dangerous
9. Investigators uncover intriguing clues to why persistent acid reflux sometimes turns into cancer
10. Pathway links inflammation, angiogenesis and breast cancer
11. Radiologists encouraged to look beyond cancer for clinically unseen diseases
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/8/2016)... ... February 08, 2016 , ... GrassrootsHealth published data from ... type 2 diabetes in the GrassrootsHealth cohort with substantially higher vitamin D levels ... in public health,” states Carole Baggerly, Director of GrassrootsHealth, “the safety and ...
(Date:2/8/2016)... ... February 08, 2016 , ... Guruji Mahendra Kumar Trivedi ... and 11th, 2016 in honor of his birthday on February 10th. During this ... Mahendra Trivedi is known by over 250,000 people from over 40 different countries as ...
(Date:2/7/2016)... ... February 07, 2016 , ... Women's Excellence staff, in all ... Day. National Wear Red Day is the first Friday each February and a ... stroke cause 1 in 3 deaths among women each year – more than all ...
(Date:2/6/2016)... ... , ... US Sports Camps is proud to sponsor the Bay Area Disc ... non-profit leaders, ultimate organizations, and coaches from around the US. The theme for this ... Director of Youth and Education, describes this year YUCC as “an important conversation we ...
(Date:2/5/2016)... ... February 05, 2016 , ... Steven Tonkinson, 36, of ... completed every year since it started in 2003. This year, he ran all 26.2 ... fellow runners and NBA team the Miami Heat. , This Sunday, while many are ...
Breaking Medicine News(10 mins):
(Date:2/8/2016)... 2016   Intarcia Therapeutics, Inc. today announced ... into the newly created role of Vice President, Head ... has two decades of leadership experience at leading pharmaceutical, ... academic medical center. Most recently Dr. Yee served as ... US Head Medical Officer at AstraZeneca, where he led ...
(Date:2/8/2016)... PAOLI, Pa. , Feb. 8, 2016  As part ... Ltd has announced today the appointment of Lori Chmura ... more than 20 years in the industry, Chmura,s extensive experience ... in the advancement of Dune Medical Devices. ... Lori will be responsible for leading all sales, marketing and ...
(Date:2/8/2016)... 2016  Avista Pharma Solutions ("Avista Pharma") announced today ... Financial Officer (CFO). Mr. Setzer is a finance and ... various roles within growing technology and life science companies. ... Executive Director of Finance at INC Research, a publicly ... . Previously, Mr. Setzer served as CFO of ...
Breaking Medicine Technology: