Reducing resistance to chemotherapy in colorectal cancer by inhibition of PHD1

August 19, 2015

Scientists at VIB and KU Leuven have shown that blocking the PHD1 oxygen sensor hinders the activation of p53, a transcription factor that aids colorectal cancer (CRC) cells in repairing themselves and thus resisting chemotherapy. Chemotherapy resistance remains a major clinical issue in the treatment of CRC. These findings indicate that PHD1 inhibition may have valuable therapeutic potential. The study was published in the leading medical journal EMBO Molecular Medicine, which features molecular biology-driven research.

Chemotherapy remains the most widely used cancer treatment, and much attention has been paid to the mechanisms underlying chemotherapy resistance. Sofie Deschoemaeker (VIB/KU Leuven) and a research team led by Massimiliano Mazzone (VIB/KU Leuven) recently investigated the interplay between p53 and the PHD family of oxygen sensors and their potential role in the response of CRC to chemotherapy.

Blocking PHD1 prevents p53 activation upon chemotherapy

The proteins PHD1, PHD2 and PHD3 are oxygen-sensitive enzymes known to be involved during cell damage and metabolic stress, such as that induced by chemotherapeutic treatment. The transcription factor p53 is a well-known cell stress sensor that, when mutated in cancer cells, can be activated to promote DNA repair in those cells, reducing chemotherapy's effectiveness. Prof. Mazzone's team found that inhibiting PHD1, but not PHD2 or PHD3, prevented p53 activation and improved the response of CRC to multiple chemotherapeutic agents.

The study's novel insight into the molecular mechanisms underlying chemotherapy resistance adds another layer of complexity to the role of PHD1 in cancer.

Robbing cancer cells of their ability to heal

Sofie Deschoemaeker: "We demonstrated that PHD1 can affect the way colorectal cancer responds to the three most common chemotherapeutic drugs used to treat CRC today. By blocking PHD1, we rob CRC cells of their ability to harness p53 to the cell-repair yoke, even when this protein is mutated (as often occurs in CRC). That means the CRC cells are exposed to the full DNA damage caused by these genotoxic drugs, resulting in greater cell death and thus a better response to the chemotherapy and, ultimately, an improved outcome."

The research, which appeared in EMBO Molecular Medicine, opens the door to the design and validation of PHD1-specific inhibitors in colorectal cancer patients, with the aim of increasing their sensitivity to currently used chemotherapeutic treatments.
-end-
Publication

PHD1 regulates p53-mediated colorectal cancer chemoresistance, Deschoemaeker et al., EMBO Molecular Medicine 2015

Questions

As this research may raise questions, we want to ask you to list the e-mail address that the VIB has made available for questions in your report or article. Everyone can contact us with questions about this research and other medical research: patients@vib.be.

VIB (the Flanders Institute for Biotechnology)

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.