Chlamydial Antiapoptotic Activity Involves Activation of the Raf/MEK/ERK Survival Pathway

Abstract

Chlamydiae are obligate intracellular bacteria that cause variety of human diseases. Chlamydia-infected host cells are profoundly resistant to apoptosis induced by many different apoptotic stimuli. The inhibition of apoptosis is thought to be an important immune escape mechanism allowing chlamydiae to productively complete their obligate intracellular growth cycle. Infection with chlamydiae can activate the Raf/MEK/ERK pathway. Because the survival pathway can modulate apoptosis, we used MEK-specific inhibitor U0126 and Raf-specific inhibitor GW5074 to examine the role of Raf/MEK/ERK pathway in chlamydial antiapoptotic activity. Apoptosis was induced by staurosporine (STS) and detected by morphology, DNA fragmentation, caspase-3 activation, and poly (ADP-ribose) polymerase cleavage. Inhibition of the pathway sensitized Chlamydia-infected cells to STS-mediated cell apoptosis. The data indicate that chlamydial antiapoptotic activity involves activation of the Raf/MEK/ERK survival pathway.

Salmonella Manipulation of Host Signaling Pathways Provokes Cellular Transformation Associated with Gallbladder Carcinoma

“…Next to S. Typhi (Caygill et al, 1994;Nath et al, 2008;Shukla et al, 2000), C. trachomatis (Arnheim Dahlströ m et al, 2011), C. pneumoniae (Zhan et al, 2011), and M. tuberculosis (Kuo et al, 2013) have reported relationships to cervical and lung cancer. Of note, these intracellular bacterial pathogens can all activate host AKT and MAPK pathways during their infection cycle (Cho et al, 2010;Du et al, 2011;Roach and Schorey, 2002). This suggests that a direct contribution of bacteria to tumor formation could be more common than previously anticipated and may potentially follow principles akin to those defined in the present study.…”

Mitogen-activated protein kinases (MAPKs) are modulated during Francisella tularensis infection, but inhibition of extracellular-signal-regulated kinases (ERKs) is of limited therapeutic benefit

“…Additionally, in vitro studies have demonstrated that MAPK activation, including ERK activation, plays an important role in F. tularensis LVS infection-induced apoptosis [32, 33]. To our knowledge, however, this is the first assessment of manipulation of ERK as a possible strategy for controlling F. tularensis infection.…”

“…Indeed, it has been suggested that the rapid proliferation of Francisella coincides with the initial activation of the apoptotic signalling pathway [35]. Therefore the relationship between ERK activation and the host mechanism of apoptosis could explain the observed differences in bacterial burden and cytokine response [33, 36]. In untreated F. tularensis infection (and in this study, in PBS-treated mice), the replication of bacteria within the lungs may induce apoptosis of infected cells such as alveolar macrophages via ERK activation, releasing the bacteria for proliferation throughout the host.…”

Vitamin K1 enhances sorafenib-induced growth inhibition and apoptosis of human malignant glioma cells by blocking the Raf/MEK/ERK pathway

“…Activated Raf phosphorylates MAPK kinase 1/2 (MEK 1/2) [4], which in turn phosphorylates and activates extracellular signal-regulated kinase 1/2 (ERK 1/2). Then, ERK activation leads to phosphorylation of a variety of transcription factors and results in induction of gene expression and proliferation [5]. The upregulation of the Raf/MEK/ERK pathway has been proven to take part in the amplification of mitogenic stimuli and promotion of cellular proliferation of malignant gliomas.…”