Role of SLC7A11/xCT in Ovarian Cancer

Abstract

Ovarian cancer is one of the most dangerous gynecologic cancers worldwide and has a high fatality rate due to diagnosis at an advanced stage of the disease as well as a high recurrence rate due to the occurrence of chemotherapy resistance. In fact, chemoresistance weakens the therapeutic effects, worsening the outcome of this pathology. Solute Carrier Family 7 Member 11 (SLC7A11, also known as xCT) is the functional subunit of the Xc- system, an anionic L-cystine/L-glutamate antiporter expressed on the cell surface. SLC7A11 expression is significantly upregulated in several types of cancers in which it can inhibit ferroptosis and favor cancer cell proliferation, invasion and chemoresistance. SLC7A11 expression is also increased in ovarian cancer tissues, suggesting a possible role of this protein as a therapeutic target. In this review, we provide an overview of the current literature regarding the role of SLC7A11 in ovarian cancer to provide new insights on SLC7A11 modulation and evaluate the potential role of SLC7A11 as a therapeutic target.

Keywords: SLC7A11; chemoresistance; compounds; non-coding RNAs; nuclear factor erythroid 2-related factor 2 (NRF2); ovarian cancer; oxidative stress; p53; reactive oxygen species (ROS); xCT.

Figure 1

Representation of the function of SLC7A11. SLC7A11 imports extracellular cystine, which is reduced to cysteine and is used in conjugation with glutamate to form γglutamylcysteine (reaction catalyzed by GLC). γGlutamylcysteine is conjugated with glycine (via GSS) to produce GSH, which is used as a cofactor for enzymes, such as GPX4, that protect cells from lipid peroxidation. In particular, GPX4 uses GSH to reduce lipid hydroperoxides (a ferroptosis inducer) to lipid alcohols, suppressing ferroptosis. In this reaction GSH is oxidized to GSSG. GSH also protects cells from ROS exposure by decreasing ROS levels. Thus, high SLC7A11 levels in cancer cells cause cell proliferation, drug resistance, cancer progression and metastasis.

Figure 2

Representation of SLC7A11 modulation in ovarian cancer cells. SLC7A11 expression can be regulated by natural (in black outside the cell) and synthetic (in red outside the cell) compounds. In addition, SLC7A11 expression can be regulated by cellular modulators, such as miR-382-5p, miR-587, miR-194-5p, circSnx12, lncRNA ADAMTS9-AS1, lncRNA SLC7A11, sterol CoA desaturase (SCD1), SNAI2, erythroblastosis virus E26 oncogene homolog 1 (Ets-1), CCAAT enhancer binding protein gamma (CEBPG) and AT-rich interacting domain containing protein 1A (ARID1A). Decreased expression of SLC7A11 causes a decrease in intracellular glutathione (GSH) levels, which favors ferroptosis, apoptosis and drug sensitivity.