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SLC transporters as a novel class of tumour suppressors: identity, function and molecular mechanisms
Yangzom D Bhutia1, Ellappan Babu1, Sabarish Ramachandran1
1Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A.
Abstract:
The role of plasma membrane transporters in cancer is receiving increasing attention in recent years. Several transporters for essential nutrients are up-regulated in cancer and serve as tumour promoters. Transporters could also function as tumour suppressors. To date, four transporters belonging to the SLC gene family have been identified as tumour suppressors. SLC5A8 is a Na(+)-coupled transporter for monocarboxylates. Among its substrates are the bacterial fermentation products butyrate and propionate and the ubiquitous metabolite pyruvate. The tumour-suppressive function of this transporter relates to the ability of butyrate, propionate and pyruvate to inhibit histone deacetylases (HDAC). SLC5A8 functions as a tumour suppressor in most tissues studied thus far, and provides a molecular link to Warburg effect, a characteristic feature in most cancers. It also links colonic bacteria and dietary fibre to the host. SLC26A3 as a tumour suppressor is restricted to colon; it is a Cl(-)/HCO(-) 3 exchanger, facilitating the efflux of HCO(-) 3 The likely mechanism for the tumour-suppressive function of SLC26A3 is related to intracellular pH regulation. SLC39A1 is a Zn(2+) transporter and its role in tumour suppression has been shown in prostate. Zn(2+) is present at high concentrations in normal prostate where it elicits its tumour-suppressive function. SLC22A18 is possibly an organic cation transporter, but the identity of its physiological substrates is unknown. As such, there is no information on molecular pathways responsible for the tumour-suppressive function of this transporter. It is likely that additional SLC transporters will be discovered as tumour suppressors in the future.
Insights
Plasma membrane transporters, particularly from the SLC gene family, are increasingly recognized for their dual roles in cancer. Some act as tumor promoters, while others, like SLC5A8, SLC26A3, SLC39A1, and SLC22A18, function as crucial tumor suppressors.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Plasma membrane transporters play a critical role in cellular nutrient uptake and waste removal.
- An increasing number of solute carrier (SLC) family transporters are being identified for their involvement in cancer development.
- While some transporters promote tumor growth, others exhibit tumor-suppressive functions.
Purpose of the Study:
- To review the current understanding of plasma membrane transporters, specifically the SLC gene family, as tumor suppressors in cancer.
- To elucidate the mechanisms and substrates involved in the tumor-suppressive roles of identified SLC transporters.
- To highlight the potential for discovering novel SLC transporters with tumor-suppressive functions.
Main Methods:
- Literature review of studies investigating SLC transporters in cancer.
- Analysis of identified SLC transporters, including SLC5A8, SLC26A3, SLC39A1, and SLC22A18.
- Examination of the molecular mechanisms underlying the tumor-suppressive functions of these transporters.
Main Results:
- SLC5A8, a monocarboxylate transporter, suppresses tumors by enabling butyrate, propionate, and pyruvate to inhibit histone deacetylases (HDACs), linking to the Warburg effect.
- SLC26A3, a chloride/bicarbonate exchanger, acts as a colon-specific tumor suppressor, likely through intracellular pH regulation.
- SLC39A1 (a zinc transporter) and SLC22A18 (an organic cation transporter) also demonstrate tumor-suppressive roles, though their mechanisms are less understood.
Conclusions:
- Specific SLC transporters (SLC5A8, SLC26A3, SLC39A1, SLC22A18) are identified as crucial tumor suppressors.
- These transporters offer potential therapeutic targets and biomarkers for various cancers.
- Further research is expected to uncover additional SLC transporters with tumor-suppressive roles.
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