BACKGROUND: The outcome of cancer therapy is greatly defined by the ability of a tumor
cell to evade treatment and re-establish its bulk mass after medical interventions.
Consequently, there is an urgent need for the characterization of molecules affecting
tumor reoccurrence. The phosphatase of regenerating liver 3 (PRL3) protein was recently
emerged among the targets that could affect such a phenomenon.
METHODS: The expression induction of PRL3 in melanoma cells treated with chemotherapeutic
agents was assessed by western blotting. The effect of PRL3 expression on cancer growth
was investigated both in vitro and in vivo. The association of PRL3 with the caveolae
structures of the plasma membrane was analyzed by detergent free raft purification.
The effect of PRL3 expression on the membrane organization was assayed by electron
microscopy and by membrane biophysical measurements. Purification of the plasma membrane
fraction and co-immunoprecipitation were used to evaluate the altered protein composition
of the plasma membrane upon PRL3 expression.
RESULTS: Here, we identified PRL3 as a genotoxic stress-induced oncogene whose expression
is significantly increased by the presence of classical antitumor therapeutics. Furthermore,
we successfully connected the presence of this oncogene with increased tumor growth,
which implies that tumor cells can utilize PRL3 effects as a survival strategy. We
further demonstrated the molecular mechanism that is connected with the pro-growth
action of PRL3, which is closely associated with its localization to the caveolae-type
lipid raft compartment of the plasma membrane. In our study, PRL3 was associated with
distinct changes in the plasma membrane structure and in the caveolar proteome, such
as the dephosphorylation of integrin beta1 at Thr788/Thr789 and the increased partitioning
of Rac1 to the plasma membrane. These alterations at the plasma membrane were further
associated with the elevation of cyclin D1 in the nucleus.
CONCLUSIONS: This study identifies PRL3 as an oncogene upregulated in cancer cells
upon exposure to anticancer therapeutics. Furthermore, this work contributes to the
existing knowledge on PRL3 function by characterizing its association with the caveolae-like
domains of the plasma membrane and their resident proteins.
