Tumor-Specific Expression of Organic Anion-Transporting Polypeptides: Transporters as Novel Targets for Cancer Therapy

Abstract

Members of the organic anion transporter family (OATP) mediate the transmembrane uptake of clinical important drugs and hormones thereby affecting drug disposition and tissue penetration. Particularly OATP subfamily 1 is known to mediate the cellular uptake of anticancer drugs (e.g., methotrexate, derivatives of taxol and camptothecin, flavopiridol, and imatinib). Tissue-specific expression was shown for OATP1B1/OATP1B3 in liver, OATP4C1 in kidney, and OATP6A1 in testis, while other OATPs, for example, OATP4A1, are expressed in multiple cells and organs. Many different tumor entities show an altered expression of OATPs. OATP1B1/OATP1B3 are downregulated in liver tumors, but highly expressed in cancers in the gastrointestinal tract, breast, prostate, and lung. Similarly, testis-specific OATP6A1 is expressed in cancers in the lung, brain, and bladder. Due to their presence in various cancer tissues and their limited expression in normal tissues, OATP1B1, OATP1B3, and OATP6A1 could be a target for tumor immunotherapy. Otherwise, high levels of ubiquitous expressed OATP4A1 are found in colorectal cancers and their metastases. Therefore, this OATP might serve as biomarkers for these tumors. Expression of OATP is regulated by nuclear receptors, inflammatory cytokines, tissue factors, and also posttranslational modifications of the proteins. Through these processes, the distribution of the transporter in the tissue will be altered, and a shift from the plasma membrane to cytoplasmic compartments is possible. It will modify OATP uptake properties and, subsequently, change intracellular concentrations of drugs, hormones, and various other OATP substrates. Therefore, screening tumors for OATP expression before therapy should lead to an OATP-targeted therapy with higher efficacy and decreased side effects.

Minireview: SLCO and ABC Transporters: A Role for Steroid Transport in Prostate Cancer Progression

“…Altered expression and distribution of various OATP transporters occurs in a number of neoplastic tissues, including gliomas, colon, breast, prostate, and hepatocellular carcinomas (13,(25)(26)(27)(28). The association of SLCO transporters with breast cancer is of particular note because it suggests an analogous role for these transporters in mediating steroid uptake into PCa.…”

Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

“…Subsequent reports revealed that the expression of OATPs may be altered in different disease conditions including cancer and may play a potential role in the development and progression of cancer as well as the disposition of anticancer drugs (2)(3)(4)(5)(6). Given that the role of OATPs in handling cancer therapeutics has been already covered by several excellent reviews (7)(8)(9)(10), this review will focus on the recent findings in the field. We will first provide a brief summary of the current understanding of the roles of OATPs on the disposition of anticancer drugs and the impact of their genetic polymorphisms on the expression and function of OATPs, as well as the use of animal models to study the role of OATPs in anticancer drug disposition.…”

In touch with your feminine side: how oestrogen metabolism impacts prostate cancer

“…Before sulphated oestrogens can be unconjugated by intracellular STS, transport of sulphated oestrogens into cells requires the expression of organic anion transporter peptides (OATP) (Raftogianis et al 2000), and indeed, several different OATPs involved in the transport of E 1 S are expressed in prostate cancers (Wright et al 2011, Buxhofer-Ausch et al 2013, Giton et al 2015. STS has been shown to be expressed in normal human prostate tissue (Reed et al 2005), prostate cancer cell lines LNCaP, DU-145 and PC3 (Nakamura et al 2006) and in primary prostate homogenates (Klein et al 1989).…”