Linking ABC transporters to the hallmarks of cancer.

Human ATP-binding cassette (ABC) transporters are ubiquitously expressed and transport a broad range of endogenous and xenobiotic substrates across extra- and intracellular membranes. Mutations in ABC genes cause 21 monogenic diseases, and polymorphisms in these genes are associated with susceptibility to complex diseases. ABC transporters also play a major role in drug bioavailability, and they mediate multidrug resistance in cancer. At least 13 ABC transporters were shown to be involved in drug resistance in vitro. In the past decade, efforts have been made to elucidate their roles in tumor biology. Herein, we explore their involvement in tumorigenesis, focusing on the hallmarks of cells as they make their way from normalcy to neoplastic growth states.

Identification of two novel heterodimeric ABC transporters in melanoma: ABCB5ß/B6 and ABCB5ß/B9.

ABCB5 is a member of the ABC transporter superfamily composed of 48 transporters, which have been extensively studied for their role in cancer multidrug resistance and, more recently, in tumorigenesis. ABCB5 has been identified as a marker of skin progenitor cells, melanoma, and limbal stem cells. It has also been associated with multidrug resistance in several cancers. The unique feature of ABCB5 is that it exists as both a full transporter (ABCB5FL) and a half transporter (ABCB5ß). Several studies have shown that the ABCB5ß homodimer does not confer multidrug resistance, in contrast to ABCB5FL. In this study, using three complementary techniques, (1) nanoluciferase-based bioluminescence resonance energy transfer, (2) coimmunoprecipitation, and (3) proximity ligation assay, we identified two novel heterodimers in melanoma: ABCB5ß/B6 and ABCB5ß/B9. Both heterodimers could be expressed in High-Five insect cells and ATPase assays revealed that both functional nucleotide-binding domains of homodimers and heterodimers are required for their basal ATPase activity. These results are an important step toward elucidating the functional role of ABCB5ß in melanocytes and melanoma.

The ß Isoform of Human ATP-Binding Cassette B5 Transporter, ABCB5ß, Localizes to the Endoplasmic Reticulum.

ABCB5ß is a member of the ABC transporter superfamily cloned from melanocytes. It has been reported as a marker of skin progenitor cells and melanoma stem cells. ABCB5ß has also been shown to exert an oncogenic activity and promote cancer metastasis. However, this protein remains poorly characterized. To elucidate its subcellular localization, we tested several anti-ABCB5 antibodies and prepared several tagged ABCB5ß cDNA constructs. We then used a combination of immunofluorescence and biochemical analyses to investigate the presence of ABCB5ß in different subcellular compartments of HeLa and MelJuSo cell lines. Treatment of the cells with the proteasome inhibitor MG132 showed that part of the population of newly synthesized ABCB5ß is degraded by the proteasome system. Interestingly, treatment with SAHA, a molecule that promotes chaperone-assisted folding, largely increased the expression of ABCB5ß. Nevertheless, the overall protein distribution in the cells remained similar to that of control conditions; the protein extensively colocalized with the endoplasmic reticulum marker calnexin. Taken together with cell surface biotinylation studies demonstrating that the protein does not reach the plasma membrane (even after SAHA treatment), the data indicate that ABCB5ß is a microsomal protein predominantly localized to the ER.

Targeting tumor resistance mechanisms.

Cancer develops resistance to treatments through many mechanisms. Single-cell analyses reveal the intratumor heterogeneity and dynamic relationships between cancer cell subpopulations. These analyses also highlight that various mechanisms of resistance may coexist in a given tumor. Studies have unraveled how the microenvironment affects tumor response to treatments and how cancer cells may adapt to these treatments. Though challenging, individualized treatment based on the molecular characterization of the tumor should become the new standard of care. In the meantime, the success rate of clinical trials in oncology remains dramatically low. There is a need to do better and improve the predictability of preclinical models. This requires innovative changes in ex vivo models and the culture system currently being used. An innovative ligand design is also urgently needed. The limited arsenal of medicinal chemistry reactions and the biases of scaffold selection favor structurally similar compounds with linear shapes at the expense of disc and spherical shapes, which leave a large chemical shape space untouched. In this regard, venoms have received increasing interest as a wellspring for drug candidates. Overall, the characterization of tumor heterogeneity has contributed to advancing our understanding of the mechanisms that underlie cancer resistance to treatments. Targeting these mechanisms will require setting key milestones to significantly improve the translatability of preclinical studies to the clinic with the hope of increasing the success rate of clinical trials.

Mammalian ABCG-transporters, sterols and lipids: To bind perchance to transport?

Members of the ATP binding cassette (ABC) transporter family perform a critical function in maintaining lipid homeostasis in cells as well as the transport of drugs. In this review, we provide an update on the ABCG-transporter subfamily member proteins, which include the homodimers ABCG1, ABCG2 and ABCG4 as well as the heterodimeric complex formed between ABCG5 and ABCG8. This review focusses on progress made in this field of research with respect to their function in health and disease and the recognised transporter substrates. We also provide an update on post-translational regulation, including by transporter substrates, and well as the involvement of microRNA as regulators of transporter expression and activity. In addition, we describe progress made in identifying structural elements that have been recognised as important for transport activity. We furthermore discuss the role of lipids such as cholesterol on the transport function of ABCG2, traditionally thought of as a drug transporter, and provide a model of potential cholesterol binding sites for ABCG2.