The Emerging Role of the SLCO1B3 Protein in Cancer Resistance

Abstract

Currently, chemotherapy is one of the mainstays of oncologic therapies. But the efficacy of chemotherapy is often limited by drug resistance and severe side effects. Consequently, it is becoming increasingly important to investigate the underlying mechanism and overcome the problem of anticancer chemotherapy resistance. The solute carrier organic anion transporter family member 1B3 (SLCO1B3), a functional transporter normally expressed in the liver, transports a variety of endogenous and exogenous compounds, including hormones and their conjugates as well as some anticancer drugs. The extrahepatic expression of SLCO1B3 has been detected in different cancer cell lines and cancer tissues. Recently, accumulating data indicates that the abnormal expression and function of SLCO1B3 are involved in resistance to anticancer drugs, such as taxanes, camptothecin and its analogs, SN-38, and Androgen Deprivation Therapy (ADT) in breast, prostate, lung, hepatic, and colorectal cancer, respectively. Thus, more investigations have been implemented to identify the potential SLCO1B3-related mechanisms of cancer drug resistance. In this review, we focus on the emerging roles of SLCO1B3 protein in the development of cancer chemotherapy resistance and briefly discuss the mechanisms of resistance. Elucidating the function of SLCO1B3 in chemoresistance may bring out novel therapeutic strategies for cancer treatment.

Mechanisms of Taxane Resistance

“…Furthermore, SNPs in the solute carrier, SLCO1B3, and the ATP-binding protein, ABCB1, lead to DTX response [476]. Interestingly, alterations in SLCO1B3 are also present in DTX resistance in prostate cancer, as described above [327,332].…”

“…Another mechanism of reducing intracellular taxane concentration and promoting resistance is to reduce the expression or activity of drug influx transporters. Evidence connects single nucleotide polymorphisms (SNPs) and loss of activity in solute carrier of organic anions (SLCO) genes with reduced response to taxanes in CRPC patients [ 326 , 327 , 328 ]. Furthermore, there are higher amounts of DTX in plasma than in the liver (where it would normally be metabolized) in Slco1b2 knockout mice ([ 329 ], reviewed in [ 330 ]); this suggests that SLCO proteins (Slco in mice) are important for transporting DTX into cells, and loss could lead to reduced intracellular DTX concentrations.…”

Comprehensive RNA-Seq Profiling Reveals Temporal and Tissue-Specific Changes in Gene Expression in Sprague–Dawley Rats as Response to Heat Stress Challenges

“…The SLCO1B3 gene encodes a liver-specific member of the organic anion transporter family, which encodes a protein that transports a variety of endogenous and exogenous compounds, including hormones and their conjugates, in addition to anticancer drugs (Sun et al, 2020). Accumulated data indicate that the abnormal expression and function of SLCO1B3 are related to resistance to anticancer drugs, and defective SLCO1B3 causes hyperbilirubinemia, rotor type (HBLRR), SLC transporter disorders, and metabolism of lipids and steroids disorders (Alencastro de Azevedo et al, 2012;Woo et al, 2017).…”

MicroRNAs in the Regulation of Solute Carrier Proteins Behind Xenobiotic and Nutrient Transport in Cells

“…Dysregulation of both miRNA and solute carrier transporters have been shown to be associated with chemoresistance ( Si et al, 2019 ; Sun et al, 2020 ; Rashid et al, 2021 ). MiR-579-3p was found to directly downregulate SLCO1B3 in pancreatic cancer cells, whereas the androgen biosynthesis inhibitor abiraterone downregulates miR-579-3p ( Barbier et al, 2021 ) ( Table 4 ).…”