Poor prognosis in cancer is typically correlated with hypoxia, a disturbance in the oxygen supply to the tumor cells. The protein PHD2 is known as a 'hypoxic sensor', as its function is highly dependent on the amount of oxygen. Researchers focused on the phosphorylation -- the addition of a phosphate group -- of this protein.
When phosphorylated, PHD2 is more active, promoting the death of cancer cells in the low-oxygen areas of the tumor. However, tumors tend to overexpress the phosphatase PP2A/B55, an enzyme that removes the phosphate group ('dephosphorylation') from PHD2. As a result, PHD2 is partially inactivated, which offsets the positive effects of this 'cancer cell killer'.
Senior author said: "Surprisingly, we found that the phosphorylation status of PHD2 is regulated by pathways such as mTOR, which in tumor and normal cells represents the main sensor of metabolic stresses such as lack of nutrients or growth factors. This means that our findings might be applied not only to cancer but also to other diseases, such inflammatory or metabolic diseases."
Authors show that PHD2 is phosphorylated on serine 125 (S125) by the mechanistic target of rapamycin (mTOR) downstream kinase P70S6K and that this phosphorylation increases its ability to degrade HIF1α. mTOR blockade in hypoxia by REDD1 restrains P70S6K and unleashes PP2A phosphatase activity. Through its regulatory subunit B55α, PP2A directly dephosphorylates PHD2 on S125, resulting in a further reduction of PHD2 activity that ultimately boosts HIF1α accumulation.
These events promote autophagy-mediated cell survival in colorectal cancer (CRC) cells. B55α knockdown blocks neoplastic growth of CRC cells in vitro and in vivo in a PHD2-dependent manner.
In the human colorectal cancer samples, the researchers discovered high expressions of PP2A/B55 in tumors compared to healthy tissues. The research is published in the leading scientific journal Cell Reports.
According to senior author: "This leads us to the conclusion that PP2A/B55 is a promising potential target for cancer therapy. That is why we started working together with an interested partner to study the potential of specific drugs against PP2A/B55. The ultimate goal is to design molecules that block the function of this phosphatase, thereby fighting cancer in a targeted way."
On top of new cancer treatment perspectives, these findings may also lead to new biomarkers: the phosphorylation status of PHD2 might be instrumental to understanding a tumor's transformation process and, consequently, to select the appropriate treatment.
http://www.vib.be/en/news/Pages/Researchers-identify-phosphorylation-process-vital-to-cancer-growth.aspx
http://www.cell.com/cell-reports/fulltext/S2211-1247(17)30108-0
Phosphorylation mechanism controlling tumor growth
- 2,277 views
- Added
Edited
Latest News
How protein synthesis in de…
By newseditor
Posted 22 Apr
Atlas of mRNA variants in d…
By newseditor
Posted 22 Apr
Mapping microbiome in metas…
By newseditor
Posted 22 Apr
Full-length mRNA packaged i…
By newseditor
Posted 22 Apr
Glucose-sensing mechanism t…
By newseditor
Posted 21 Apr
Other Top Stories
Immunotherapy against clotting factor to protect neuroinflammation…
Read more
How gene activity shapes immunity across species
Read more
Glutamine metabolism affects T cell signaling and function
Read more
Nature of immune cells in the human brain disclosed
Read more
Immune cells could hold key to therapies for spinal cord injuries
Read more
Protocols
A programmable targeted pro…
By newseditor
Posted 23 Apr
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Publications
Neuronal activity rapidly r…
By newseditor
Posted 22 Apr
A perspective on muscle phe…
By newseditor
Posted 22 Apr
Foxp1 suppresses cortical a…
By newseditor
Posted 22 Apr
Single-cell long-read seque…
By newseditor
Posted 22 Apr
Unlocking potential: the ro…
By newseditor
Posted 22 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar