Abstract
BackgroundThe 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.MethodsThe 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.ResultsHere, 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 β1 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.ConclusionsThis 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.
Highlights
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
phosphatase of regenerating liver 3 (PRL3) protein expression is induced upon treatment with anticancer drugs Considering that key observations concerning the oncogenic action of PRL3 were made in B16 melanoma cells [18, 19], we chose to perform our studies in these cells by using the B16F0 line
In the light of the previously observed elevation of PRL3 expression in noncancerous MEF cells exposed to genotoxic carcinogens [20], we sought to find out if such phenomenon could be detected in B16F0 cells as well
Summary
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. Understanding and targeting the tumor survival strategies which counterbalance a chemotherapeutic treatment could supplement classical therapy and influence the outcome of the disease. Among the targets that could affect such a phenomenon, the family of dual specificity phosphatases of regenerating liver (PRL) has received great attention in the recent years since their members, especially the phosphatase of regenerating liver 3 (PRL3), appeared to play a role in a wide range of cancerous processes [1, 2]. PRL3 was associated with primary tumor growth, tumor reoccurrence, and therapy resistance in many human cancers. Its expression was associated with increased tumor growth in primary gastric tumors [3] This protein was suggested as a marker to predict the relapse of gastric cancer [4] and invasive breast cancer [5]. A chemical inhibitor of PRL3 was identified as a potent adjuvant to enhance the effectivity of cisplatin treatment in lung cancer cells [10], and the depletion of endogenous PRL3 was observed to sensitize acute myeloid leukemia cell to doxorubicin treatment [11]
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