Recently biomechanics of cancer cells, in particular stiffness or elasticity, has been identified as an important factor relating to cancer cell function, adherence, motility, transformation and invasion. We report on the nanomechanical responses of metastatic cancer cells and benign mesothelial cells taken from human body cavity fluids using atomic force microscopy. Following our initial study (Cross et al 2007 Nat. Nanotechnol. 2 780-3), we report on the biophysical properties of patient-derived effusion cells and address the influence of cell morphology on measured cell stiffness. Using a cytocentrifugation method, which yields morphologically indistinguishable cells that can be prepared in 1 min and avoids any possible artifacts due to 12 h ex vivo culture, we find that metastatic tumor cells are more than 80% softer than benign cells with a distribution over six times narrower than that of normal cells. Consistent with our previous study, which yielded distinguishable cell populations based on ex vivo growth and morphological characteristics, our results show it is unlikely that morphology alone is sufficient to explain the difference in elastic moduli for these two cell types. Moreover, analysis of non-specific cell adhesion inherent to tumor and normal cells collected from patients show surface adhesion of tumor cells is ∼33% less adhesive compared to that of normal cells. Our findings indicate that biomechanical-based functional analysis may provide an additional platform for cytological evaluation and diagnosis of cancer in the future.
SARS-CoV-2 is the cause of the ongoing Coronavirus Disease 2019 (COVID-19) pandemic. Understanding of the RNA virus and its interactions with host proteins could improve therapeutic interventions for COVID-19. Using icSHAPE, we determined the structural landscape of SARS-CoV-2 RNA in infected human cells and from refolded RNAs, as well as of the regulatory untranslated regions of SARS-CoV-2 and six other coronaviruses. We validated several structural elements predicted in silico and discovered structural features that affect the translation and abundance of subgenomic viral RNAs in cells. The structural data informed a deep learning tool to predict 42 host proteins that bind to SARS-CoV-2 RNA. Strikingly, antisense oligonucleotides targeting the structural elements and FDA-approved drugs inhibiting the SARS-CoV-2 RNA binding proteins dramatically reduced SARS-CoV-2 infection in cells derived from human liver and lung tumors. Our findings thus shed light on coronavirus and reveal multiple candidate therapeutics for COVID-19 treatment.
Actin was first identified in non-muscle cells only about three decades ago, and at about the same time, it was found that actin filaments were disrupted in the malignant transformed cells. The actin network is a rather complex, yet important structural and functional system of all eukaryotic cells. Actin filaments provide the basic infrastructure for maintaining cell morphology and functions such as adhesion, motility, exocytosis, endocytosis, and cell division. Growing evidence from this laboratory and others shows that alterations of actin polymerization, or actin remodeling, plays a pivotal role in regulating the morphologic and phenotypic events of a malignant cell. Actin remodeling is the result of activation of oncogenic actin signaling pathways (e.g., Ras and Src), or inactivation of several important actin-binding proteins that have tumor suppressor functions (e.g., gelsolin). Distinctive protein expression patterns of some of these genes in cancer and progressive carcinogenic processes have been observed. It has become evident that actin dynamics are regulated by a complex interplay of the small GTPase proteins of Ras superfamily Rac, Rho, and Cdc42, and efforts to develop specific inhibitors for these small G proteins as anticancer drug are underway. In this review we will discuss how actin remodeling is altered in the malignant transformation process, the functional significance of actin alteration in association with malignant phenotypes, and the approaches of targeting actin remodeling for chemopreventive and chemotherapeutic drug development. Approaches including using nature products directly modulating actin polymerization, using inhibitors of actin pathway small G proteins, and using gene-augmentation for actin binding proteins will be discussed. In addition, the concept of using F/G-actin ratio as a surrogate marker for actin-pathway based therapy will also be introduced.
Constitutive nuclear factor-KB (NF-KB) activation is observed in androgen-independent prostate cancer and represents a predictor for biochemical recurrence after radical prostatectomy. Dietary agents such as pomegranate extract (PE) have received increasing attention as potential agents to prevent the onset or progression of many malignancies, including prostate cancer. Here, we show that PE inhibited NF-KB and cell viability of prostate cancer cell lines in a dose-dependent fashion in vitro. Importantly, maximal PE-induced apoptosis was dependent on PE-mediated NF-KB blockade. In the LAPC4 xenograft model, PE delayed the emergence of LAPC4 androgen-independent xenografts in castrated mice through an inhibition of proliferation and induction of apoptosis. Moreover, the observed increase in NF-KB activity during the transition from androgen dependence to androgen independence in the LAPC4 xenograft model was abrogated by PE. Our study represents the first description of PE as a promising dietary agent for the prevention of the emergence of androgen independence that is driven in part by heightened NF-KB activity. [Mol Cancer Ther 2008;7(9):2662 -71]
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