SLC12A4

Serine is a vital amino acid in tumorigenesis. While cells can perform de novo serine synthesis, most transformed cells rely on serine uptake to meet their increased biosynthetic requirements. Solute carriers (SLCs), a family of transmembrane nutrient transport proteins, are the gatekeepers of amino acid acquisition and exchange in mammalian cells and are emerging as anticancer therapeutic targets; however, the SLCs that mediate serine transport in cancer cells remain unknown. Here we perform an arrayed RNAi screen of SLC-encoding genes while monitoring amino acid consumption and cell proliferation in colorectal cancer cells using metabolomics and high-throughput imaging. We identify SLC6A14 and SLC25A15 as major cytoplasmic and mitochondrial serine transporters, respectively. We also observe that SLC12A4 facilitates serine uptake. Dual targeting of SLC6A14 and either SLC25A15 or SLC12A4 diminishes serine uptake and growth of colorectal cancer cells in vitro and in vivo, particularly in cells with compromised de novo serine biosynthesis. Our results provide insight into the mechanisms that contribute to serine uptake and intracellular handling.

The solute carrier family 12 (SLC12) of cation-chloride cotransporters (CCCs) comprises potassium chloride cotransporters (KCCs, e.g. KCC1, KCC2, KCC3, and KCC4)-mediated Cl^- extrusion, and sodium potassium chloride cotransporters (N[K]CCs, NKCC1, NKCC2, and NCC)-mediated Cl^- loading. The CCCs play vital roles in cell volume regulation and ion homeostasis. Gain-of-function or loss-of-function of these ion transporters can cause diseases in many tissues. In recent years, there have been considerable advances in our understanding of CCCs' control mechanisms in cell volume regulations, with many techniques developed in studying the functions and activities of CCCs. Classic approaches to directly measure CCC activity involve assays that measure the transport of potassium substitutes through the CCCs. These techniques include the ammonium pulse technique, radioactive or nonradioactive rubidium ion uptake-assay, and thallium ion-uptake assay. CCCs' activity can also be indirectly observed by measuring γ-aminobutyric acid (GABA) activity with patch-clamp electrophysiology and intracellular chloride concentration with sensitive microelectrodes, radiotracer ³⁶Cl^-, and fluorescent dyes. Other techniques include directly looking at kinase regulatory sites phosphorylation, flame photometry, ²²Na⁺ uptake assay, structural biology, molecular modeling, and high-throughput drug screening. This review summarizes the role of CCCs in genetic disorders and cell volume regulation, current methods applied in studying CCCs biology, and compounds developed that directly or indirectly target the CCCs for disease treatments.

KCC-1, a nanostructured silica material with a bicontinuous concentric lamellar (bcl) morphology, provides plenty of functional characteristics, such as an open channel structure, excellent accessibility, and a large surface area. Although bcl silica exhibits various superior properties, studies on its morphology and its application in dye-sensitized solar cells (DSSCs) are still limited. Therefore, this work aims to study the influence of the synthesis time on the morphology of bcl silica. Moreover, we used the synthesized bcl silica as internal micro-reflectors in DSSCs. The bcl silica was synthesized using the reflux method by varying synthesis times. The morphology of bcl silica was observed using FESEM and HRTEM. FESEM images show that bcl silica has bicontinuous lamellar walls arranged concentrically to form spherical particles. As the synthesis time increases, the average particle size of bcl silica increases. The quantization of bcl silica binary images shows that the average lamellar cross-sectional area ratio decreases with increasing synthesis time. The simulation of the Cahn-Hilliard's spinodal decomposition model using MATLAB also describes the lamellar cross-sectional area ratio of bcl silica. In addition, to characterize the FESEM image's texture, a Shannon entropy calculation was performed. The line and circular gray value intensity profiles of the HRTEM image show that bcl silica has a denser core than the outer part. The denser core proves that the lamellae in bcl silica are concentrically arranged towards the particle core. Furthermore, we added bcl silica to a photoanode to see the effect of bcl characteristics on the DSSC performance. The results show that the bcl silica significantly improves the light-harvesting efficiency in DSSCs due to its low refractive index and open channel structure.