ABC transporters and the hallmarks of cancer: roles in cancer aggressiveness beyond multidrug resistance

Abstract

The ATP-binding cassette transporters (ABC transporters) have been intensely studied over the past 50 years for their involvement in the multidrug resistance (MDR) phenotype, especially in cancer. They are frequently overexpressed in both naive and post-treatment tumors, and hinder effective chemotherapy by reducing drug accumulation in cancer cells. In the last decade however, several studies have established that ABC transporters have additional, fundamental roles in tumor biology; there is strong evidence that these proteins are involved in transporting tumor-enhancing molecules and/or in protein-protein interactions that impact cancer aggressiveness, progression, and patient prognosis. This review highlights these studies in relation to some well-described cancer hallmarks, in an effort to re-emphasize the need for further investigation into the physiological functions of ABC transporters that are critical for tumor development. Unraveling these new roles offers an opportunity to define new strategies and targets for therapy, which would include endogenous substrates or signaling pathways that regulate these proteins.

Keywords: ABC transporters; cancer aggressiveness; hallmarks of cancer.

Figure 1

Example of a 3-membrane spanning domains (MSDs) transporter, showing two nucleotide binding domains (NBD) and coupling helices that transmit the “power strokes” from the dimerization of the two NBDs. The membrane spanning cylindrical objects represent the alpha helices protein domains.

Figure 2

Representation of the two transporter mechanism of action models. (A) ATP switch model hypothesis showing the binding and hydrolysis of ATP to ADP at the two nucleotide binding domains (NBDs). This causes inversion of the transporter’s conformation and alternating access model. This inversion of the transporter results in two different substrate affinities which allow the binding (B) and unbinding of substrates.

Figure 3

A schematic representation of hallmarks of cancer (HoC) and the ABC transporters that have been shown to promote them. Some of the HoC like angiogenesis and metabolic reprogramming are yet to be associated with the dysregulation of ABC transporters.