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.
Phosphorylation mechanism controlling tumor growth
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