Chemotherapy induced PRL3 expression promotes cancer growth via plasma membrane remodeling and specific alterations of caveolae-associated signaling

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.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0264-8) contains supplementary material, which is available to authorized users.

Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer

“…Among the non-HGSOC cell lines both A2780 (i.e., endometrioid cancer) and A2780cp20 also had detectable PTP4A3 mRNA levels. PTP4A3 mRNA levels were higher in the drug resistant COV362-47R relative to the parental COV362 cells ( Figure 1 B) ( p < 0.05) consistent with the suggestion that drug resistance is associated with elevated PTP4A3 expression [ 26 ], although this did not appear to be translated into higher protein levels ( Figure 1 C and Supplementary Figure S2 ). HGSOC is considered to be intrinsically drug-resistant and of the HGSOC established cell lines, Kuramochi cells appeared to have the highest mRNA levels of all of the cells examined while OVCAR4 cells had the highest PTP4A3 protein levels ( Figure 1 C and Supplementary Figure S2 ).…”

“…Unlike many other oncogenic proteins, PTP4A3 is rarely mutated; rather, the high protein levels result from gene amplification, increased transcription and translation, and possibly altered protein degradation [ 11 ]. It is noteworthy that PTP4A3 has been reported to be induced by genotoxic stress caused by cancer chemotherapeutic agents such as cisplatin, etoposide and doxorubicin [ 26 ]. We found that cell lines derived from HGSOC tumors express higher PTP4A3 mRNA levels than other histologic subtypes of OvCa or nonmalignant HIO-180 cells and had high PTP4A3 protein levels ( Figure 1 C).…”

PRL3 induces polyploid giant cancer cells eliminated by PRL3-zumab to reduce tumor relapse

“…Interestingly, PRL3 induces a stem cell-like transcriptional program in acute myeloid leukemia (AML) by upregulating LIN28B, a stem cell reprogramming factor 11 . More recently, PRL3 expression was induced upon genotoxic stress to promote cancer growth and survival 12 .…”

BCAR1 plays critical roles in the formation and immunoevasion of invasive circulating tumor cells in lung adenocarcinoma

“…A previous study has reported that BCAR1 and RAC1 also regulate cell movement and adhesion 36 . Specifically, RAC1-mediated cell migration is initiated by BCAR1 37 . Furthermore, the BCAR1/Rac1 axis can suppress colorectal cancer and metastasis through the Hippo, ERK, and PAK signaling pathways 38 , indicating the signaling pathway is indispensable in cell signal transduction.…”