P130Cas translocates into the nucleus upon fluid shear stress application and alleviates NF-κB activity in osteocytes.

The physical properties of the extracellular matrix (ECM), such as stiffness, are involved in the determination of the characteristics of cancer cells, including chemotherapy sensitivity. Resistance to chemotherapy is often linked to dysfunction of tumor suppressor p53; however, it remains elusive whether the ECM microenvironment interferes with p53 activation in cancer cells. Here, we show that, in MCF-7 breast cancer cells, extracellular stiffness influences p53 activation induced by the antitumor drug doxorubicin. Cell growth inhibition by doxorubicin was increased in response to ECM rigidity in a p53-dependent manner. The expression of Rho-associated coiled coil-containing protein kinase (ROCK) 2, which induces the activation of myosin II, was significantly higher when cells were cultured on stiffer ECM substrates. Knockdown of ROCK2 expression or pharmacological inhibition of ROCK decreased doxorubicin-induced p53 activation. Our results suggest that a soft ECM causes downregulation of ROCK2 expression, which drives resistance to chemotherapy by repressing p53 activation.

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATL). The trans-activator protein Tax of HTLV-1 is thought to play a crucial role in the early-stage transformation of the virus-infected cells. Tax is a multi-functional protein and modulates cellular signaling pathways that promote proliferation and survival of HTLV-1-infected cells, primarily through the trans-activation of cellular target genes. Tax interacts with a variety of host cell factors including signal transducers and transcription factors, leading to the activation of transcription factors such as CREB, NF-κB, and SRF and activates both its own promoter and those of a variety of host cellular genes. Tax activates its own promoter mainly through CREB and host cellular genes through NF-κB, SRF, and CREB. Accumulating evidence indicates that the Tax-mediated trans-activation of target genes through NF-κB plays an essential role in the transformation of HTLV-1 infected cells. However, the repertoire of Tax target genes, especially those crucial for leukemogenesis, are not known in detail. In this review, we summarize transcriptional activation mechanisms and target genes of Tax, especially focusing on transformation, to facilitate understanding of the underlying mechanisms of leukemogenesis induced by HTLV-1 infection.

Multinucleation occurs in various types of advanced cancers and contributes to their malignant characteristics, including anticancer drug resistance. Therefore, inhibiting multinucleation can improve cancer prognosis; however, the molecular mechanisms underlying multinucleation remain elusive. Here, we introduced a genetic mutation in cervical cancer cells to induce cell fusion-mediated multinucleation. The olfactory receptor OR1N2 was heterozygously mutated in these fused cells; the same OR1N2 mutation was detected in multinucleated cells from clinical cervical cancer specimens. The mutation-induced structural change in the OR1N2 protein activated protein kinase A (PKA), which, in turn, mediated the non-canonical olfactory pathway. PKA phosphorylated and activated furin protease, resulting in the cleavage of the fusogenic protein syncytin-1. Because this cleaved form of syncytin-1, processed by furin, participates in cell fusion, furin inhibitors could suppress multinucleation and reduce surviving cell numbers after anticancer drug treatment. The improved anticancer drug efficacy indicates a promising therapeutic approach for advanced cervical cancers.