Ferroptosis, a form of iron-dependent cell death driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated as a tumor-suppressor function for cancer therapy. Recent advance revealed that the sensitivity to ferroptosis is tightly linked to numerous biological processes, including metabolism of amino acid and the biosynthesis of glutathione. Here, by using a high-throughput CRISPR/Cas9-based genetic screen in HepG2 hepatocellular carcinoma cells to search for metabolic proteins inhibiting ferroptosis, we identified a branched-chain amino acid aminotransferase 2 (BCAT2) as a novel suppressor of ferroptosis. Mechanistically, ferroptosis inducers (erastin, sorafenib, and sulfasalazine) activated AMPK/SREBP1 signaling pathway through iron-dependent ferritinophagy, which in turn inhibited BCAT2 transcription. We further confirmed that BCAT2 as the key enzyme mediating the metabolism of sulfur amino acid, regulated intracellular glutamate level, whose activation by ectopic expression specifically antagonize system Xc^– inhibition and protected liver and pancreatic cancer cells from ferroptosis in vitro and in vivo. On the contrary, direct inhibition of BCAT2 by RNA interference, or indirect inhibition by blocking system Xc^– activity, triggers ferroptosis. Finally, our results demonstrate the synergistic effect of sorafenib and sulfasalazine in downregulating BCAT2 expression and dictating ferroptotic death, where BCAT2 can also be used to predict the responsiveness of cancer cells to ferroptosis-inducing therapies. Collectively, these findings identify a novel role of BCAT2 in ferroptosis, suggesting a potential therapeutic strategy for overcoming sorafenib resistance.

Conventional cancer treatments, such as surgical resection, radiotherapy, and chemotherapy, have achieved significant progress in cancer therapy. Nevertheless, some limitations (such as toxic side effects) are still existing for conventional therapies, which motivate efforts toward developing novel theranostic avenues. Owning many merits such as easy surface modification, unique optical properties, and high biocompatibility, gold nanoparticles (AuNPs and GNPs) have been engineered to serve as targeted delivery vehicles, molecular probes, sensors, and so on. Their small size and surface characteristics enable them to extravasate and access the tumor microenvironment (TME), which is a promising solution to realize highly effective treatments. Moreover, stimuli-responsive properties (respond to hypoxia and acidic pH) of nanoparticles to TME enable GNPs’ unrivaled control for effective transport of therapeutic cargos. In this review article, we primarily introduce the basic properties of GNPs, further discuss the recent progress in gold nanoparticles for cancer theranostics, with an additional concern about TME stimuli-responsive studies.

Zeolitic imidazolate framework (ZIF-8), composed of zinc ion and dimethylimidazole, is widely used in drug delivery, due to the easy fabrication process and the good biosafety. However, ZIF-8 suffers from low affinity to non-electric-rich drugs and does not have surface functional groups. Here, to target deliver doxorubicin (DOX) with ZIF-8, DOX was firstly modified with pH-sensitive linker containing two carboxyl groups to form the inactive prodrug CAD and subsequently seeded inside ZIF-8 by a 5 min mineralization process. CAD has high affinity to ZIF-8 due to the carboxyl groups and can anchor to the ZIF-8 surface to enable the surface modification with folic acid for tumor targeting. Moreover, the DOX release is precisely controlled by three steps of acidic pH-response, with the dissociation of FA layer, the breakdown of ZIF-8 structure, and the cleavage of pH-sensitive linker in prodrug. This novel “prodrug-ZIF-8” strategy has opened new horizon in drug delivery.

Differentiated cancer cells reacquiring stem cell traits following radiotherapy may enrich cancer stem cells and accelerate tumor recurrence and metastasis. We are interested in the mechanistic role of dying cells-derived HMGB1 in CD133⁻ pancreatic cancer cells dedifferentiation following radiotherapy. We firstly confirmed that X-ray irradiation induced differentiation of CD133⁻ pancreatic cancer cells, from either sorted from patient samples or established cell lines, into cancer stem-like cells (iCSCs). Using an in vitro coculture model, X-ray irradiation induced dying cells to release HMGB1, which further promoted CD133⁻ pancreatic cancer cells regaining stem cell traits, such as higher sphere forming ability and expressed higher level of stemness-related genes and proteins. Inhibiting the expression and activity of HMGB1 attenuated the dedifferentiation stimulating effect of irradiated, dying cells on C133⁻ pancreatic cancer cells in vitro and in PDX models. Mechanistically, HMGB1 binding with TLR2 receptor functions in a paracrine manner to affect CD133⁻ pancreatic cancer cells dedifferentiation via activating Hippo-YAP pathway and HIF-1α expression in oxygen independent manner in vitro and in vivo. We conclude that X-ray irradiation induces CD133⁻ pancreatic cancer cell dedifferentiation into a CSC phenotype, and inhibiting HMGB1 may be a strategy to prevent CSC enrichment and further pancreatic carcinoma relapse.

Background: Mesenchymal cancer cells, resistant to the traditional regulated cell death, are exquisitely vulnerable to ferroptosis. However, the underlying mechanism has been rarely studied. While glycolipid metabolism rewiring is a critical determination of both cancer cell mesenchymal phenotype and cell death resistance, we are interested in the underlying cross talk between glycolipid metabolism and mesenchymal cancer cell ferroptosis sensitivity.

Tumor metastasis is driven by malignant cells and stromal cell components of the tumor microenvironment. Cancer stem cells (CSCs) are thought to be responsible for metastasis by altering the tumor microenvironment. Epithelial-mesenchymal transition (EMT) processes contribute to specific stages of the metastatic cascade, promoted by cytokines and chemokines secreted by stromal cell components in the tumor microenvironment. C-C chemokine receptor 7 (CCR7) interacts with its ligand, chemokine ligand 21(CCL21), to mediate metastasis in some cancer cells lines. This study investigated the role of CCL21/CCR7 in promoting EMT and metastasis of cluster of differentiation 133⁺ (CD133⁺) pancreatic cancer stem-like cells. Panc-1, AsPC-1, and MIA PaCa-2 pancreatic cancer cells were selected because of their aggressive invasive potentials. CCR7 expression levels were examined in total, CD133⁺ and CD133⁻ cell fractions by Immunofluorescence analysis and real time-quantitative polymerase chain reaction (RT-qPCR). The role of CCL21/CCR7 in mediating metastasis and survival of CD133⁺ pancreatic cancer stem-like cells was detected by Transwell assays and flow cytometry, respectively. EMT and lymph node metastasis related markers (E-cadherin, N- cadherin, LYVE-1) were analyzed by western blot. CCR7 expression levels were analyzed by immunohistochemical staining and RT-qPCR in resected tumor tissues, metastatic lymph nodes, normal lymph nodes and adjacent normal tissues from patients with pancreatic carcinoma. CCR7 expression was significantly increased in CD133⁺ pancreatic cancer stem-like cells, resected pancreatic cancer tissues, and metastatic lymph nodes, compared with CD133⁻ cancer cells, adjacent normal tissues and normal lymph nodes, respectively. CCL21/CCR7 promoted metastasis and survival of CD133⁺ pancreatic cancer stem-like cells and regulated CD133⁺ pancreatic cancer stem-like cells metastasis by modulating EMT and Erk/NF-κB pathway. These results indicate a specific role for CCL21/CCR7 in promoting EMT and metastasis in CD133⁺ pancreatic cancer stem-like cells. Furthermore the data also indicated the potential importance of developing therapeutic strategies targeting cancer stem-like cells and CCL21/CCR7 for reducing metastasis.