In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2, no specific and effective drugs for treating this disease have been reported until today. Angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2, mediates the virus infection by binding to spike protein. Although ACE2 is expressed in the lung, kidney, and intestine, its expressing levels are rather low, especially in the lung. Considering the great infectivity of COVID-19, we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection. Here, we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein. The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody, Meplazumab, inhibits SARS-CoV-2 amplification. Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells, which can be neutralized by CD147 extracellular fragment. Viral loads are detectable in the lungs of human CD147 (hCD147) mice infected with SARS-CoV-2, but not in those of virus-infected wild type mice. Interestingly, virions are observed in lymphocytes of lung tissue from a COVID-19 patient. Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dose-dependent manner, which is specifically inhibited by Meplazumab. Furthermore, CD147 mediates virus entering host cells by endocytosis. Together, our study reveals a novel virus entry route, CD147-spike protein, which provides an important target for developing specific and effective drug against COVID-19.

SUMMARY Ferroptosis, a cell death process driven by cellular metabolism and iron-dependent lipid peroxidation, is implicated in various diseases such as ischemic organ damage and cancer 1 , 2 . As a central regulator of ferroptosis, the enzyme glutathione peroxidase 4 (GPX4) protects cells from ferroptosis by neutralizing lipid peroxides, which are byproducts of cellular metabolism; as such, inhibiting GPX4 directly, or indirectly by depriving its substrate glutathione or building blocks of glutathione (such as cysteine), can trigger ferroptosis 3 . Ferroptosis contributes to the antitumour function of multiple tumour suppressors including p53, BAP1, and fumarase 4 - 7 . Counterintuitively, mesenchymal cancer cells, which are prone to metastasis and often resistant to various treatments, have shown to be highly susceptible to ferroptosis 8 , 9 . Here, we demonstrate that ferroptosis can be regulated non-cell autonomously by cadherin-mediated intercellular contacts. In epithelial cells, E-cadherin-mediated intercellular interaction suppresses ferroptosis through intracellular Merlin-Hippo signalling. Antagonizing this signalling axis unleashes the activity of the proto-oncogenic transcriptional co-activator YAP to promote ferroptosis through upregulation of multiple ferroptosis modulators, including acyl-CoA synthetase long chain family member 4 (ACSL4) and transferrin receptor. This finding provides mechanistic insights into the observations that epithelial mesenchymal transition (EMT)/metastasis-prone cancer cells are highly sensitive to ferroptosis 8 . Importantly, the regulation of ferroptosis by cell-cell contact and Merlin-YAP signalling is not limited to epithelial cells; a similar mechanism also modulates ferroptosis in some non-epithelial cells. Finally, we found that genetic inactivation of the tumour suppressor Merlin, a frequent tumourigenic event in mesothelioma 10 , 11 , renders cancer cells more sensitive to ferroptosis in an orthotopic mouse model of malignant mesothelioma. Together, this study unveils the role of intercellular interaction and intracellular Merlin-YAP signalling in dictating ferroptotic death; it also suggests that malignant mutations in Merlin-YAP signalling can serve as biomarkers predicting cancer cell responsiveness to future ferroptosis-inducing therapies.

Ferroptosis, a form of regulated necrosis driven by iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various signaling pathways related to cancer. In this study, we found that activating mutation of phosphatidylinositol 3-kinase (PI3K) or loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function, highly frequent events in human cancer, confers ferroptosis resistance in cancer cells, and that inhibition of the PI3K-AKT-mTOR signaling axis sensitizes cancer cells to ferroptosis induction. Mechanistically, this resistance requires sustained activation of mTORC1 and the mechanistic target of rapamycin (mTOR)C1-dependent induction of sterol regulatory element-binding protein 1 (SREBP1), a central transcription factor regulating lipid metabolism. Furthermore, stearoyl-CoA desaturase-1 (SCD1), a transcriptional target of SREBP1, mediates the ferroptosis-suppressing activity of SREBP1 by producing monounsaturated fatty acids. Genetic or pharmacologic ablation of SREBP1 or SCD1 sensitized ferroptosis in cancer cells with PI3K-AKT-mTOR pathway mutation. Conversely, ectopic expression of SREPB1 or SCD1 restored ferroptosis resistance in these cells, even when mTORC1 was inhibited. In xenograft mouse models for PI3K-mutated breast cancer and PTEN-defective prostate cancer, the combination of mTORC1 inhibition with ferroptosis induction resulted in near-complete tumor regression. In conclusion, hyperactive mutation of PI3K-AKT-mTOR signaling protects cancer cells from oxidative stress and ferroptotic death through SREBP1/SCD1-mediated lipogenesis, and combination of mTORC1 inhibition with ferroptosis induction shows therapeutic promise in preclinical models.

The antimalarial drug artemisinin and its derivatives have been explored as potential anticancer agents, but their underlying mechanisms are controversial. In this study, we found that artemisinin compounds can sensitize cancer cells to ferroptosis, a new form of programmed cell death driven by iron-dependent lipid peroxidation. Mechanistically, dihydroartemisinin (DAT) can induce lysosomal degradation of ferritin in an autophagy-independent manner, increasing the cellular free iron level and causing cells to become more sensitive to ferroptosis. Further, by associating with cellular free iron and thus stimulating the binding of iron-regulatory proteins (IRPs) with mRNA molecules containing iron-responsive element (IRE) sequences, DAT impinges on IRP/IRE-controlled iron homeostasis to further increase cellular free iron. Importantly, in both in vitro and a mouse xenograft model in which ferroptosis was triggered in cancer cells by the inducible knockout of GPX4, we found that DAT can augment GPX4 inhibition-induced ferroptosis in a cohort of cancer cells that are otherwise highly resistant to ferroptosis. Collectively, artemisinin compounds can sensitize cells to ferroptosis by regulating cellular iron homeostasis. Our findings can be exploited clinically to enhance the effect of future ferroptosis-inducing cancer therapies.

Although chemotherapy, targeted therapy and endocrine therapy decrease rate of disease recurrence in most breast cancer patients, many patients exhibit acquired resistance. Hyperactivation of the PI3K/AKT/mTOR pathway is associated with drug resistance and cancer progression. Currently, a number of drugs targeting PI3K/AKT/mTOR are being investigated in clinical trials by combining them with standard therapies to overcome acquired resistance in breast cancer. In this review, we summarize the critical role of the PI3K/AKT/mTOR pathway in drug resistance, the development of PI3K/AKT/mTOR inhibitors, and strategies to overcome acquired resistance to standard therapies in breast cancer.

Abstract-Atherosclerosis and arterial injury-induced neointimal hyperplasia involve medial smooth muscle cell (SMC) proliferation and migration into the arterial intima. Because many 7-transmembrane and growth factor receptors promote atherosclerosis, we hypothesized that the multifunctional adaptor proteins ␤-arrestin1 and -2 might regulate this pathological process. Deficiency of ␤-arrestin2 in ldlr Ϫ/Ϫ mice reduced aortic atherosclerosis by 40% and decreased the prevalence of atheroma SMCs by 35%, suggesting that ␤-arrestin2 promotes atherosclerosis through effects on SMCs. To test this potential atherogenic mechanism more specifically, we performed carotid endothelial denudation in congenic wild-type, ␤-arrestin1 Ϫ/Ϫ , and ␤-arrestin2 Ϫ/Ϫ mice. Neointimal hyperplasia was enhanced in ␤-arrestin1mice, and diminished in ␤-arrestin2 Ϫ/Ϫ mice. Neointimal cells expressed SMC markers and did not derive from bone marrow progenitors, as demonstrated by bone marrow transplantation with green fluorescent protein-transgenic cells. Moreover, the reduction in neointimal hyperplasia seen in ␤-arrestin2 Ϫ/Ϫ mice was not altered by transplantation with either wild-type or ␤-arrestin2 Ϫ/Ϫ bone marrow cells. After carotid injury, medial SMC extracellular signal-regulated kinase activation and proliferation were increased in ␤-arrestin1Ϫ/Ϫ and decreased in ␤-arrestin2 Ϫ/Ϫ mice. Concordantly, thymidine incorporation and extracellular signal-regulated kinase activation and migration evoked by 7-transmembrane receptors were greater than wild type in ␤-arrestin1 Ϫ/Ϫ SMCs and less in ␤-arrestin2 Ϫ/Ϫ SMCs. Proliferation was less than wild type in ␤-arrestin2 Ϫ/Ϫ SMCs but not in ␤-arrestin2 Ϫ/Ϫ endothelial cells. We conclude that ␤-arrestin2 aggravates atherosclerosis through mechanisms involving SMC proliferation and migration and that these SMC activities are regulated reciprocally by ␤-arrestin2 and ␤-arrestin1. These findings identify inhibition of ␤-arrestin2 as a novel therapeutic strategy for combating atherosclerosis and arterial restenosis after angioplasty.

It is well documented that hypoxia activates the hypoxia-inducible factor 1-alpha (HIF1α)/vascular endothelial growth factor A (VEGFA) axis to promote angiogenesis in breast cancer. However, it is unclear how this axis is negatively regulated. In this study, we demonstrated that miR-153 directly inhibits expression of HIF1α by binding to the 3′UTR of HIF1A mRNA, as well as suppresses tube formation of primary human umbilical vein endothelial cells (HUVECs) and breast cancer angiogenesis by decreasing the secretion of VEGFA. Importantly, expression of miR-153 was induced by hypoxia-stimulated ER stress, which activates IRE1α and its downstream transcription factor X-box binding protein 1 (XBP1). X-box binding protein 1 directly binds to the promoter of the miR-153 host gene PTPRN and activates transcription. These results indicate that hypoxia induces miR-153 to fine tune the HIF1α/VEGFA axis in breast cancer angiogenesis and miR-153 could be used for breast cancer anti-angiogenesis therapy.

Biased agonism, the ability of different ligands for the same receptor to selectively activate some signaling pathways while blocking others, is now an established paradigm for G protein-coupled receptor signaling. One group of receptors in which endogenous bias is critical is the chemokine system, consisting of over 50 ligands and 20 receptors that bind one another with significant promiscuity. We have previously demonstrated that ligands for the same receptor can cause biased signaling responses. The goal of this study was to identify mechanisms that could underlie biased signaling between different receptor splice variants. The C-X-C motif chemokine receptor 3 (CXCR3) has two splice variants, CXCR3A and CXCR3B, which differ by 51 amino acids at its N-terminus. Consistent with an earlier study, we found that C-X-C motif chemokine ligands 4, 9, 10, and 11 all activated G at CXCR3A, while at CXCR3B these ligands demonstrated no measurable G or G activity.-arrestin (arr) was recruited at a reduced level to CXCR3B relative to CXCR3A, which was also associated with differences in arr2 conformation.arr2 recruitment to CXCR3A was attenuated by both G protein receptor kinase (GRK) 2/3 and GRK5/6 knockdown, while only GRK2/3 knockdown blunted recruitment to CXCR3B. Extracellular regulated kinase 1/2 phosphorylation downstream from CXCR3A and CXCR3B was increased and decreased, respectively, by arr1/2 knockout. The splice variants also differentially activated transcriptional reporters. These findings demonstrate that differential splicing of CXCR3 results in biased responses associated with distinct patterns ofarr conformation and recruitment. Differential splicing may serve as a common mechanism for generating biased signaling and provides insights into how chemokine receptor signaling can be modulated post-transcriptionally.