Poor prognosis in cancer is typically correlated with hypoxia, a
disturbance in the oxygen supply to the tumor cells. Scientists at VIB-KU Leuven have identified a new mechanism that
impacts tumor growth.
The typical lack of oxygen in tumors doesn’t only
stimulate proliferation, but also offsets the important role of the
protein PHD2 as ‘cancer cell killer’. A possible solution lies in
blocking the enzyme PP2A/B55, which restores the function of PHD2 and
consequently slows down cancer growth. The research, led by prof.
Massimiliano Mazzone (VIB-KU Leuven), is published in the leading
scientific journal Cell Reports.
‘When phosphorylated, PHD2 protein is more active, promoting the death of
cancer cells in the low-oxygen areas of the tumor.’
The protein PHD2 is
known as a ‘hypoxic sensor’, as its function is highly dependent on the
amount of oxygen. In the VIB-KU Leuven Center for Cancer Biology, Dr.
Giusy Di Conza and colleagues, led by prof. Massimiliano Mazzone,
focused on the phosphorylation – the addition of a phosphate group –
of this protein.
Interfering in phosphorylation process
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’.
Prof. Massimiliano Mazzone (VIB-KU Leuven): “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.”
Phosphatase as a cancer target
During the research, prof. Mazzone’s lab collaborated closely with
several domestic and foreign researchers. In particular, the German ISAS
lab (Dortmund) and the Leuven University Hospital played decisive
roles, with the latter providing the human cancer samples necessary for
the research. In these samples, the researchers discovered high
expressions of PP2A/B55 in tumors compared to healthy tissues.
Prof. Massimiliano Mazzone (VIB-KU Leuven): “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.”
Assessing the effects of future drugs
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.
Prof. Massimiliano Mazzone (VIB-KU Leuven): “To fully understand all
the ins and outs of these processes, we also need to take a closer look
at the tumor microenvironment and the immune system. After all, they
strongly impact tumor growth. As we speak, we are defining the role of
PP2A/B55 in both the tumor microenvironment.