Effective ferroptotic small-cell lung cancer cell death from SLC7A11 inhibition by sulforaphane

Abstract

Small-cell lung cancer (SCLC) is a highly aggressive cancer with poor prognosis, due to a lack of therapeutic targets. Sulforaphane (SFN) is an isothiocyanate derived from cruciferous vegetables and has shown anticancer effects against numerous types of cancer. However, its anticancer effect against SCLC remains unclear. The present study aimed to demonstrate the anticancer effects of SFN in SCLC cells by investigating cell death (ferroptosis, necroptosis and caspase inhibition). The human SCLC cell lines NCI-H69, NCI-H69AR (H69AR) and NCI-H82 and the normal bronchial epithelial cell line, 16HBE14o-were used to determine cell growth and cytotoxicity, evaluate the levels of iron and glutathione, and quantify lipid peroxidation following treatment with SFN. mRNA expression levels of cystine/glutamate antiporter xCT (SLC7A11), a key component of the cysteine/glutamate antiporter, were measured using reverse transcription-quantitative PCR, while the levels of SLC7A11 protein were measured using western blot analysis. Following the addition of SFN to the cell culture, cell growth was significantly inhibited, and cell death was shown in SCLC and multidrug-resistant H69AR cells. The ferroptotic effects of SFN were confirmed following culture with the ferroptosis inhibitor, ferrostatin-1, and deferoxamine; iron levels were elevated, which resulted in the accumulation of lipid reactive oxygen species. The mRNA and protein expression levels of SLC7A11 were significantly lower in SFN-treated cells compared with that in the control cells (P<0.0001 and P=0.0006, respectively). These results indicated that the anticancer effects of SFN may be caused by ferroptosis in the SCLC cells, which was hypothesized to be triggered from the inhibition of mRNA and protein expression levels of SLC7A11. In conclusion, the present study demonstrated that SFN-induced cell death was mediated via ferroptosis and inhibition of the mRNA and protein expression levels of SLC7A11 in SCLC cells. The anticancer effects of SFN may provide novel options for SCLC treatment.

The Trace Element Selenium Is Important for Redox Signaling in Phorbol Ester-Differentiated THP-1 Macrophages

“…How exactly PMA stimulates NRF2 activation is not known. However, a similar controversial regulation of NRF2 target gene subsets has also been observed with other small molecule inducers of NRF2, such as Bay 11-7085 [49] and sulforaphane [50], which stimulate ferroptosis and induce a strong upregulation of HMOX1 with concomitant downregulation of other NRF2 target genes like GPX4 and SLC7A11, respectively. Depending on the point of attack, small molecule inducers of NRF2 might therefore reveal a specific profile of NRF2 target gene regulation.…”

Prognostic and Immunological Role of Key Genes of Ferroptosis in Pan-Cancer

“…SLC7A11 was overexpressed in non-small cell lung cancer (NSCLC) tissues and its overexpression was significantly correlated with poor prognosis of NSCLC patients ( Ji et al, 2018 ). Inhibition of SLC7A11 by sulforaphane or YTHDC2 (a m6A reader) induced the ferroptosis of lung cancer cells and suppressed the progression of lung cancer ( Hu et al, 2020 ; Iida et al, 2021 ; Ma et al, 2021 ). Interestingly, our results also showed that AIFM2 was overexpressed in ESCA and HNSC; however, up to now, the roles and mechanisms of AIFM2 in the progression of ESCA and HNSC were still unknown.…”

Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy

“…Various approaches have been developed to target this pathway as an anticancer strategy [ 226 , 227 , 228 , 229 , 230 , 231 ]. xCT inhibitors, such as sulfasalazine [ 232 , 233 , 234 ] and erastin [ 235 , 236 , 237 , 238 , 239 ], can reduce GSH and increase ROS in cancer cells, propagating iron-dependent lipid peroxidation that leads to tumor ferroptosis. Since inhibition of xCT alone may force cancer cells to import cysteine via other amino acid transporters such as alanine/serine/cysteine/threonine transporters (ASCT1 and ASCT2), xCT inhibitors are often used in combination with other chemotherapeutic agents or radiotherapy to overcome drug resistance.…”