Penn researchers identify secondary pathway for survival of cancer cells

July 16, 2003

(Philadelphia, PA) - Researchers at the Abramson Family Cancer Research Institute at the University of Pennsylvania have determined that a key enzyme, Pim-2, is responsible for the survival of cancer cells. The finding - which will appear in the August 1 edition of the journal Genes & Development - represents an important advance in understanding why cancer cells survive in the body (working against the body's natural immune system), before growing into tumors. It also answers a 20-year-old question as to the purpose of Pim-2, an enzyme present in high concentrations in many tumors, but left unstudied to this time; and it equates Pim-2 with another, more commonly studied survival pathway, the Akt-enzyme pathway.

"This finding is important because it shows, for the first time, how Pim-2 works and its key role in cancer cell survival," said Craig Thompson, MD, Principal Investigator of the study and Scientific Director of the Abramson Family Cancer Research Institute (AFCRI). "Up until now, predominant thinking has looked to the Akt pathway as the primary pathway for cancer cells. Now we know that Pim-2 plays an equally important role - and it is as much of a cancer-promoting gene, or oncogene, as Akt.

"Our next step is to try and manipulate the action of Pim-2, so that we can interfere with the survival of cancer cells," said Thompson. "Ultimately, the hope is that this could lead to new, targeted therapies for killing cancer cells before they turn into deadly tumors that can spread elsewhere in the body."

Pim-2 was originally identified, in 1984, as a serine/threonine kinase, one of several hundred principal oncogenes under investigation for their role in cancer cell survival and growth. Its mutated form has been observed in high quantities in cases of prostate cancer, leukemia and multiple myeloma. Close to 50 kinases are thought to play a key role in cancer progression. Through a process of elimination, scientists test each oncogene for its role or function in cancer progression, manipulating each gene, to see which changes, called mutations, allow the cell to live, and which ones let the cell die.

In the presence of Pim-2, sixty per cent of cancer cells survived attempts to starve or kill the cell. Cancer cells survived for the maximum duration in the study - up to three weeks - with Pim-2 present, regardless of whether or not growth factor (food for the cell) was present. Only when both the Akt pathway and Pim-2 pathway were dysregulated (no longer functioning inside the cell), were cancerous cells unable to survive and died. The Akt pathway is well studied because it plays many roles in cancer progression, including a key role in cancer cell survival.

Both Pim-2 and Akt survival pathways were found to operate independently; Pim-2 was not activated by any of the Akt pathway regulating enzymes - PI3K, HSP-90 and TOR. While Akt interacts with other enzymes to promote cell survival, the function of Pim-2 is independent, with no other enzymes required. The pathways were shown to be distinct by their response to the antibiotic rapamycin: Akt is sensitive to rapamycin and Pim-2 is not. Rapamycin is a commonly used drug for treatment of transplant patients, it restrains the body's immune response from rejecting foreign growths, such as a new organ. Pim-2 overcomes this potent inhibitor of cell survival.

While these pathways appeared distinct, they are not completely different and both have some common actions. One factor shared by both pathways is a phosphorylated "off signal" suppressor protein called 4E-BP1. Suppressor genes prevent the cancer cell from growing, so when turned "off", the cell can grow.

Exposing the role of Pim-2 was accomplished through the latest technology for cancer research, a micro-array analysis of RNA in the immune systems of mice.

Penn scientists focused their research on the question of why cancer cells survive - and not simply removed from the body by the immune system. For tumor cells to grow, they must have the ability to ignore "death signals" that would cause them to die, and not promote cancer. Pim-2 had been shown as an important gene in causing tumors in mouse experiments, and was also present in large amounts in tumors. Over-production of Pim-2 allows the cells to ignore or become insensitive to boosters of the immune system, such as the antibiotic rapamycin.

The study took two years to complete (mid-2000 to mid-2002). Funding was provided through grants from the National Cancer Institute and the AFCRI.
-end-
Editor's Note:

You may also find this news release with photos available on-line at http://www.uphs.upenn.edu/news

PENN Medicine is a $2.2 billion enterprise dedicated to the related missions of medical education, biomedical research, and quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System (created in 1993 as the nation's first integrated academic health system).

Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1400 fulltime faculty and 700 students, Penn's School of Medicine is recognized worldwide for its superior education and training of the next generation of physician/scientists and leaders of academic medicine.

Penn's Health System consists of four hospitals (including its flagship Hospital of the University of Pennsylvania, consistently rated one of the nation's "Honor Roll" hospitals by U.S. News & World Report); a faculty practice plan, a primary-care provider network, three multispecialty satellite facilities, and home healthcare and hospice.

University of Pennsylvania School of Medicine

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.