Plasma Membrane Transporters as Biomarkers and Molecular Targets in Cholangiocarcinoma

Abstract

The dismal prognosis of patients with advanced cholangiocarcinoma (CCA) is due, in part, to the extreme resistance of this type of liver cancer to available chemotherapeutic agents. Among the complex mechanisms accounting for CCA chemoresistance are those involving the impairment of drug uptake, which mainly occurs through transporters of the superfamily of solute carrier (SLC) proteins, and the active export of drugs from cancer cells, mainly through members of families B, C and G of ATP-binding cassette (ABC) proteins. Both mechanisms result in decreased amounts of active drugs able to reach their intracellular targets. Therefore, the “cancer transportome”, defined as the set of transporters expressed at a given moment in the tumor, is an essential element for defining the multidrug resistance (MDR) phenotype of cancer cells. For this reason, during the last two decades, plasma membrane transporters have been envisaged as targets for the development of strategies aimed at sensitizing cancer cells to chemotherapy, either by increasing the uptake or reducing the export of antitumor agents by modulating the expression/function of SLC and ABC proteins, respectively. Moreover, since some elements of the transportome are differentially expressed in CCA, their usefulness as biomarkers with diagnostic and prognostic purposes in CCA patients has been evaluated.

Heat Shock Protein 90 Triggers Multi-Drug Resistance of Ovarian Cancer via AKT/GSK3β/β-Catenin Signaling

“…Ectopic expression of ABC transports is regarded as the main reason of MDR ( 20 , 45 ). To explore the mechanism of Hsp90 in MDR in ovarian cancer, the expressions of P-gp and BCRP were determined.…”

Sorafenib Chemosensitization by Caryophyllane Sesquiterpenes in Liver, Biliary, and Pancreatic Cancer Cells: The Role of STAT3/ABC Transporter Axis

“…Hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA) and ductal adenocarcinoma (PDAC) are examples of tumors in which ABC transporters play this dual role; in particular, an upregulation of MDR1 and MRP1 is correlated with a more aggressive phenotype of these cancers, characterized by reduced differentiation, larger tumors, and the presence of microvascular invasion, while MRP2 expression has been mainly associated with poorer response to antitumor drugs [20,[27][28][29]. Therefore, targeting ABC transporter function and expression could represent an important strategy to fight cancer progression and to overcome chemoresistance, thus increasing the anticancer drug effectiveness at low doses and reducing the chemotherapy side effects.…”

“…Taking into account the results obtained in the combination experiments that showed a potentiation of sorafenib cytotoxicity by caryophyllane sesquiterpenes, especially βcaryophyllene oxide, and the recognized involvement of ABC-transporters and STAT3 signaling in the progression and chemoresistance of hepato-biliary-pancreatic cancers [27][28][29][30][31][32][33], a possible modulation by treatments of this cascade in Bx-PC3, associated with the observed changes in MDR1 and MRPs pumps, was also evaluated (Figure 11). Activation of STAT3 by phosphorylation at tyrosine 705 (phospho(Tyr705)-STAT3), which is known to play an important role in the control of cell survival, proliferation, and apoptosis [34], has been measured.…”

Overcome Drug Resistance in Cholangiocarcinoma: New Insight Into Mechanisms and Refining the Preclinical Experiment Models

“…Generally, anti-cancer drugs are transported intracellularly by plasma membrane transporters that belong to the solute carrier (SLC) superfamily of proteins ( 93 ), and the active drugs are exported out of cancer cells through several members of the families of ATP-binding cassette (ABC) proteins, such as ABCB, ABCC and ABCG. Both downregulated expression or impaired function of SLC protein and increased expression or enhanced function of ABC family in CCA reduce intracellular concentration of active drugs, thereby causing drug resistance ( 94 ).…”