Oncogenic PI3K promotes methionine dependency in breast cancer cells through the cystine-glutamate antiporter xCT

Abstract

The precursor homocysteine is metabolized either through the methionine cycle to produce methionine or through the transsulfuration pathway to synthesize cysteine. Alternatively, cysteine can be obtained through uptake of its oxidized form, cystine. Many cancer cells exhibit methionine dependency such that their proliferation is impaired in growth media in which methionine is replaced by homocysteine. Here, we showed that oncogenic PIK3CA and decreased expression of SLC7A11, a gene that encodes a cystine transporter also known as xCT, correlated with increased methionine dependency in breast cancer cells. Oncogenic PIK3CA was sufficient to confer methionine dependency to mammary epithelial cells, in part by decreasing cystine uptake through the transcriptional and posttranslational inhibition of xCT. Manipulation of xCT activity altered the proliferation of breast cancer cells in methionine-deficient, homocysteine-containing media, suggesting that it functionally contributed to methionine dependency. We propose that concurrent with decreased cystine uptake through xCT, PIK3CA mutant cells use homocysteine through the transsulfuration pathway to synthesize cysteine. Consequently, less homocysteine is available to produce methionine, contributing to methionine dependency. These results indicate that oncogenic PIK3CA alters methionine and cysteine utilization, in part by inhibiting xCT, to contribute to the methionine dependency phenotype in breast cancer cells.

Methionine Dependence of Cancer

“…The differential metabolic fates of homocysteine in methionine-dependent (transsulfuration) and -independent cells (mainly methionine cycle) observed in breast cancer cell systems may be a general feature of the Hoffman effect. Indeed, similar redirection of homocysteine into the transsulfuration branch is induced by oncogenic PI3K mutations, which induce a methionine-dependent phenotype when expressed in methionine-independent cells (Figure 2A) [10]. It is interesting to note that the transsulfuration pathway is largely restricted to pancreas, liver, and kidney, but is active in cancer cells [8,[35][36][37], which could contribute to the differential response of cancer cells to growth in homocysteine medium.…”

“…As indicated above, generation of methionine stress resistant cancer cells is usually coupled with loss of tumorigenic properties such as the ability of anchorage independent growth and proliferation in 1% serum. Conversely, oncogenic mutations in phosphoinositide 3-kinase (PI3K) and H-ras expression have been shown to promote methionine dependence [10,33]. Whether other oncogenes induce a similar metabolic dependence has not been systematically investigated, but these experiments indicate a tight link between methionine dependence and tumorigenicity.…”

High cell density increases glioblastoma cell viability under glucose deprivation via degradation of the cystine/glutamate transporter xCT (SLC7A11)

“…The component of class III phosphatidylinositol 3-kinase complex BECN1 binds to xCT when it is phosphorylated by AMPK and negatively regulates xCT activity (49). The activity of xCT is also negatively regulated by phosphorylation on serine 26 in the N-terminal cytosolic region (50,51), although it is unclear whether this affects xCT protein stability.…”

TGF-β1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells

“…For example, epidermal growth factor receptor 11 and CD44 variants 12 directly interact with xCT and stabilize its expression at the cell surface, which enhances antioxidant capacity. In contrast, oncogenic PI3KCA inhibits xCT and promotes methionine dependency in mammary epithelial tumors 13 , and 5′ adenosine monophosphate-activated protein kinase (AMPK)-mediated phosphorylation of Beclin-1 promote ferroptosis via complexation with xCT 14 . xCT expression is transcriptionally activated by nuclear factor erythroid 2related factor 2 (Nrf2) and activating transcription factor 4 (ATF4) under conditions of oxidative stress or hypoxia 15,16 , whereas it is inhibited by the tumor suppressor TP53 following reactive oxygen species (ROS)induced stress independent of its functions regulating apoptosis and senescence 17 . Taken together, these findings indicate that xCT expression is precisely regulated by various growth-regulating signals to meet genetic, metabolic, and environmental needs.…”