Dual Function of Par3 in Tumorigenesis.

Cell maintenance and the establishment of cell polarity involve complicated interactions among multiple protein complexes as well as the regulation of different signaling pathways. As an important cell polarity protein, Par3 is evolutionarily conserved and involved in tight junction formation as well as tumorigenesis. In this review, we aimed to explore the function of Par3 in tumorigenesis. Research has shown that Par3 exhibits dual functions in human cancers, both tumor-promoting and tumor-suppressive. Here, we focus on the activities of Par3 in different stages and types of tumors, aiming to offer a new perspective on the molecular mechanisms that regulate the functions of Par3 in tumor development. Tumor origin, tumor microenvironment, tumor type, cell density, cell-cell contact, and the synergistic effect of Par3 and other tumor-associated signaling pathways may be important reasons for the dual function of Par3. The important role of Par3 in mammalian tumorigenesis and potential signaling pathways is context dependent.

uPAR: An Essential Factor for Tumor Development.

Tumorigenesis is closely related to the loss of control of many genes. Urokinase-type plasminogen activator receptor (uPAR), a glycolipid-anchored protein on the cell surface, is controlled by many factors in tumorigenesis and is expressed in many tumor tissues. In this review, we summarize the regulatory effects of the uPAR signaling pathway on processes and factors related to tumor progression, such as tumor cell proliferation, adhesion, metastasis, glycolysis, tumor microenvironment and angiogenesis. Overall, the evidence accumulated to date suggests that uPAR induction by tumor progression may be one of the most important factors affecting therapeutic efficacy. An improved understanding of the interactions between uPAR and its coreceptors in cancer will provide critical biomolecular information that may help to better predict the disease course and response to therapy.

Inhibition of herpes simplex virus 1 by cepharanthine via promoting cellular autophagy through up-regulation of STING/TBK1/P62 pathway.

Cepharanthine (CEP), a naturally occurring isoquinoline alkaloid extracted from the genus CEP of the Tetrandrine family, was reported to possess many biological activities such as anti-inflammatory, antitumor, antiviral, and immune-enhancing effects. Nevertheless, the underlying mechanisms of CEP against herpes simplex virus type 1 (HSV-1) are still elusive. In this study, we explored the anti-HSV effects and mechanisms of CEP in vitro. The results showed that CEP possessed a strong inhibitory effect against HSV-1 infection with the TC50 of 5.4 µg/mL, the IC50 of 0.835 µg/mL, and the TI of 6.47. Most importantly, CEP could promote the phosphorylation of STING, TBK1, and P62 and the expression of LC3II without induction of interferon by directly targeting the STING/TBK1/P62 signaling pathways. Electron microscopy showed that autophagy induced by CEP could degrade viral particles and cellular components. RT-PCR results revealed that a sharp reduction of large numbers of virus gene transcription in 16 h after CEP treatment. Furthermore, CEP also reduced the HSV-1 gB and gC transcription. In conclusion, one of the effects of CEP was to promote interferon-independent autophagy through STING mediated signaling.

Emodin Induces Apoptosis of Colon Cancer Cells via Induction of Autophagy in a ROS-Dependent Manner.

Recent studies revealed that emodin extracted from Chinese herbs exhibits an anticancer effect on different cancer types, including colon cancer. However, the mechanism is not well understood. In our study, we confirmed that emodin treatment inhibited cell viability and induced apoptosis in colon cancer cells. Further experiments found that emodin was also able to induce autophagy, which is indispensible for apoptosis induced by emodin. More interestingly, emodin treatment also results in mitochondrial dysfunction and ROS accumulation in colon cancer cells. Finally, we stressed that ROS accumulation is essential for autophagy and apoptosis induced by emodin. In conclusion, emodin induces apoptosis in colon cancer cells through induction of autophagy, during which ROS generation is of the essence. Our findings improve understanding of emodin's effect on colon cancer suppression and provide a new theoretical basis for colon cancer therapy.

Inhibition of Cdc42 is essential for Mig-6 suppression of cell migration induced by EGF.

The adaptor protein Mig-6 is a negative regulator of EGF signaling. It is shown that Mig-6 inhibits cell migration via direct interaction with the ErbB receptors, thereby inhibiting cross-phosphorylation or targeting the receptors for degradation. Mig-6 has also been shown to bind to and inhibit the Rho GTPase Cdc42 to suppress cytoskeletal rearrangement. However, the molecular mechanism(s) by which Mig-6 inhibits cell migration via Cdc42 is still not entirely clear. Here, we show that Mig-6 binding to Cdc42 is necessary and sufficient to inhibit EGF-induced filopodia formation and migration. This binding, mediated by four specific residues (I11, R12, M26, R30) in the Mig-6 CRIB domain, is essential for Mig-6 function. In addition, ectopic expression of Cdc42 reverses Mig-6 inhibition of cell migration. Mig-6 CRIB domain, alone, is sufficient to inhibit cell migration. Conversely, Mig-6 binding to EGFR is dispensable for Mig-6-mediated inhibition of cell migration. Moreover, we found that decreased Mig-6 expression correlates with cancer progression in breast and prostate cancers. Together, our results demonstrate that Mig-6 inhibition of Cdc42 signaling is critical in Mig-6 function to suppress cell migration and that dysregulation of this pathway may play a critical role in cancer development.