The xc− cystine/glutamate antiporter: a mediator of pancreatic cancer growth with a role in drug resistance

Abstract

The x c − cystine transporter enhances biosynthesis of glutathione, a tripeptide thiol important in drug resistance and cellular defense against oxidative stress, by enabling cellular uptake of cystine, a rate-limiting precursor. Because it is known to regulate glutathione levels and growth of various cancer cell types, and is expressed in the pancreas, we postulate that it is involved in growth and drug resistance of pancreatic cancer. To examine this, we characterised expression of the x c − transporter in pancreatic cancer cell lines, MIA PaCa-2, PANC-1 and BxPC-3, as subjected to cystine-depletion and oxidative stress. The results indicate that these cell lines depend on x c − -mediated cystine uptake for growth, as well as survival in oxidative stress conditions, and can modulate x c − expression to accommodate growth needs. Immunohistochemical analysis showed that the transporter was differentially expressed in normal pancreatic tissues and overexpressed in pancreatic cancer tissues from two patients. Furthermore, gemcitabine resistance of cells was associated with elevated x c − expression and specific x c − inhibition by monosodium glutamate led to growth arrest. The results suggest that the x c − transporter by enhancing glutathione biosynthesis plays a major role in pancreatic cancer growth, therapy resistance and represents a potential therapeutic target for the disease.

Chemotherapy triggers HIF-1–dependent glutathione synthesis and copper chelation that induces the breast cancer stem cell phenotype

“…*P < 0.05, **P < 0.01, ***P < 0.001 vs. NTC Pac (-); # P < 0.05, ## P < 0. SSA or BSO, respectively, potentiates the anticancer effect of chemotherapy on breast cancer cell lines (38,39). Our results demonstrate that targeting the glutathione synthesis pathway also decreases the number of BCSCs, which are required for breast cancer recurrence and metastasis.…”

Amino Acid Transporters in Cancer and Their Relevance to “Glutamine Addiction”: Novel Targets for the Design of a New Class of Anticancer Drugs

“…In addition to promoting tumor growth via mechanisms involving antioxidant machinery both inside and outside the cells and autocrine glutamate signaling, SLC7A11 also induces chemoresistance to selective drugs (28,(32)(33)(34). The underlying mechanism in this process also involves the ability of the transporter to modulate oxidative stress.…”

Antitumor activity of nifurtimox is enhanced with tetrathiomolybdate in medulloblastoma

“…HERPUD1 expression is upregulated in response to the accumulation of unfolded proteins in the endoplasmic reticulum (ER) as part of the ER stress response (64). SLC7A11 is a member of the heteromeric Na + -independent anionic amino acid transport system, where it exchanges cystine for glutamate, which ultimately enhances glutathione synthesis (65). Of these, SLC7A11 was up-regulated similarly by nifurtimox and nifurtimox plus TM treatment, while HERPUD1 and particularly ATF3 were more up-regulated by the nifurtimox plus TM combination treatment.…”