Pharmacologic inhibition of PARP is the primary therapeutic strategy for BRCA mutant ovarian cancer. However, most of patients carry wild-type BRCA1/2 with no significant clinical benefits from PARP inhibitors, calling for the needs to further understanding and developing new strategy when employing PARP inhibitors to treat ovarian cancer. Here, we show that ferroptosis, a form of regulated cell death driven by iron-dependent phospholipid peroxidation, is partly responsible for the efficacy of PARP inhibitor olaparib. Mechanistically, pharmacological inhibition or genetic deletion of PARP downregulates the expression of cystine transporter SLC7A11 in a p53-dependent manner. Consequently, decreased glutathione biosynthesis caused by SLC7A11 repression promotes lipid peroxidation and ferroptosis. Furthermore, ferroptosis perturbation results in significant resistance to olaparib without affecting DNA damage response, while boosting ferroptosis by ferroptosis inducers (FINs) synergistically sensitizes BRCA-proficient ovarian cancer cells and xenografts to PARP inhibitor. Together, our results reveal a previously unappreciated mechanism coupling ferroptosis to PARP inhibition and suggest the combination of PARP inhibitor and FINs in the treatment of BRCA-proficient ovarian cancer.

Metastasis of cancer cells is believed to be influenced by many factors which progress through several stages as cancer cells move from a primary lesion to metastatic sites. One of those factors, cell motility, plays an important role in the progression, especially after the extravasation. Motility-related protein 1 (MRP-1/CD9), which belongs to the transmembrane 4 superfamily of membrane proteins, is considered to inhibit cell motility (Miyake et al, 1991). It has been demonstrated that the cells which expressed MRP-1/CD9 by transfection showed suppressed cell motility in vitro (Ikeyama et al, 1993). An inverse correlation was found between MRP-1/CD9 expression and metastases in breast cancer , and reduced MRP-1/CD9 gene expressions resulted in poor prognoses in non-small cell lung cancer . KAI1/CD82 is also one of the transmembrane 4 superfamily of membrane proteins which has similar effects, mediating metastasis and correlating positively with good prognosis in patients with nonsmall cell lung cancer (Adachi et al, 1996) and inversely with metastasis in prostatic cancers (Dong et al, 1995;Dong, 1996). There were no studies of MRP-1/CD9 and KAI1/CD82 in oesophageal cancer. In this paper, we investigated expressions of MRP-1/CD9 and KAI1/CD82 in oesophageal cancer. MATERIALS AND METHODS Clinical materialsTissues, whose expressions of MRP-1/CD9 and KAI1/CD82 were examined, were obtained from oesophageal cancer specimens of 108 and 104 patients, respectively, who underwent oesophagectomy at our institution, from June 1987 to December 1995. The operative techniques were as previously described (Imamura et al, 1987). Some samples were not available to conduct immunohistochemical staining, therefore the number of the cases examined in MRP-1/CD9 and KAI1/CD82 was not identical. All resected tumours were microscopically examined to identify histologic type, extent and mode of cancer invasion, and metastasis to lymph nodes. In some cases lymphatic invasion could be seen in the apparent absence of lymph node metastases. Considering this, we investigated the correlation between the expression of MRP-1/CD9 and lymphatic invasion in 98 out of 108 patients. Nine patients were excluded because lymphatic invasion could not be conclusively determined.Histologically, all of the patients had squamous cell carcinoma. No adenosquamous carcinoma or small cell variants were found. Tumour staging was based on the pTNM pathological classification system (Hermanek et al, 1987). The 5-year survival rates of all patients who received curative resections were examined.Specimens were fixed in a 10% formaldehyde solution and embedded in paraffin. Four-micrometre sections were cut and mounted on glass slides. Summary Although the mechanisms of action of the transmembrane superfamilies, motility-related protein-1 (MRP-1/CD9) and KAI1/CD82, are not well known, they are reported to suppress the metastasis of several kinds of cancers. The suppression of cell motility by MRP-1/CD9 may cause suppression of the metastasis. As we could not find any ...

Ferroptosis, a form of regulated cell death triggered by lipid peroxidation, was recently identified as an important mechanism in radiotherapy (RT)-mediated tumor suppression and radioresistance, although the exact genetic contexts in which to target ferroptosis in RT remains to be defined. p53 is the most commonly mutated gene in human cancers and a major effector to RT. Here, we identify ferroptosis as a critical mechanism to mediate p53 function in tumor radiosensitivity. Mechanistically, RT-mediated p53 activation antagonizes RT-induced SLC7A11 expression and represses glutathione synthesis, thereby promoting RT-induced lipid peroxidation and ferroptosis. p53 deficiency promotes radioresistance in cancer cells or tumors at least partly through SLC7A11-mediated ferroptosis inhibition. Ferroptosis inducers (FINs) that inhibit SLC7A11 exert significant radiosensitizing effects in tumor organoids and patient-derived xenografts with p53 mutation or deficiency. Finally, we show that RT-induced ferroptosis correlates with p53 activation and better clinical outcomes to RT in cancer patients. Together, our study uncovers a previously unappreciated role of ferroptosis in p53-mediated radiosensitization and suggest using FINs in combination with RT to treat p53-mutant cancers.

In the EVOLVE China trial, the SYNERGY bioabsorbable polymer-coated EES was noninferior to the PROMUS Element Plus permanent polymer-coated EES for the primary endpoint of late loss at nine months.