AKT-dependent nuclear localization of EPRS1 activates PARP1 in breast cancer cells.

Glutamyl-prolyl-tRNA synthetase (EPRS1) is a bifunctional aminoacyl-tRNA-synthetase (aaRS) essential for decoding the genetic code. EPRS1 resides, with seven other aaRSs and three noncatalytic proteins, in the cytoplasmic multi-tRNA synthetase complex (MSC). Multiple MSC-resident aaRSs, including EPRS1, exhibit stimulus-dependent release from the MSC to perform noncanonical activities distinct from their primary function in protein synthesis. Here, we show EPRS1 is present in both cytoplasm and nucleus of breast cancer cells with constitutively low phosphatase and tensin homolog (PTEN) expression. EPRS1 is primarily cytosolic in PTEN-expressing cells, but chemical or genetic inhibition of PTEN, or chemical or stress-mediated activation of its target, AKT, induces EPRS1 nuclear localization. Likewise, preferential nuclear localization of EPRS1 was observed in invasive ductal carcinoma that were also P-Ser473-AKT+. EPRS1 nuclear transport requires a nuclear localization signal (NLS) within the linker region that joins the catalytic glutamyl-tRNA synthetase and prolyl-tRNA synthetase domains. Nuclear EPRS1 interacts with poly(ADP-ribose) polymerase 1 (PARP1), a DNA-damage sensor that directs poly(ADP-ribosyl)ation (PARylation) of proteins. EPRS1 is a critical regulator of PARP1 activity as shown by markedly reduced ADP-ribosylation in EPRS1 knockdown cells. Moreover, EPRS1 and PARP1 knockdown comparably alter the expression of multiple tumor-related genes, inhibit DNA-damage repair, reduce tumor cell survival, and diminish tumor sphere formation by breast cancer cells. EPRS1-mediated regulation of PARP1 activity provides a mechanistic link between PTEN loss in breast cancer cells, PARP1 activation, and cell survival and tumor growth. Targeting the noncanonical activity of EPRS1, without inhibiting canonical tRNA ligase activity, provides a therapeutic approach potentially supplementing existing PARP1 inhibitors.

Short-Term Efficacy and Adverse Effects of Sulfasalazine in the Management of Axial Spondyloarthropathy.

INTRODUCTION: Ankylosing spondylitis (AS) is an inflammatory spondyloarthropathy that involves the sacroiliac joints and the axial skeleton. Sulfasalazine's efficacy in treating the axial symptoms of AS has been a subject of controversy. METHODS: This prospective observational study recruited AS patients and categorized them into two groups: the first group had AS for less than or equal to four years and the second group had AS for more than four years. Erythrocytic sedimentation rate (ESR) and C-reactive protein (CRP) levels were recorded at baseline and at six-month follow-up. Disease severity was assessed using the ankylosing spondylitis disease activity score (ASDAS), Bath ankylosing spondylitis disease activity index (BASDAI) score, and Bath ankylosing spondylitis functional index (BASFI) score. RESULTS: A total of 33 patients diagnosed with AS were recruited in this study, mostly males (88%) and within 21-30 years of age. ESR and CRP values were measured at baseline and at six months post-treatment with sulfasalazine. Mean ESR and mean CRP values showed a statistically significant reduction of 43.5% (p=0.001) and 58.45% (p=0.0012) respectively, at the 6-month follow-up. Four patients (12.12%) reported gastrointestinal intolerance. The mean reduction in the ASDAS score was 24% (p=0.002), the BASDAI score was 40.08% (p=0.001), and the BASFI score was 39.54% (p=0.01). Additionally, the duration of symptoms did not appear to influence with efficacy of sulfasalazine. DISCUSSION: Sulfasalazine is a safe alternative therapy for patients with AS who cannot afford biologics, due to its reasonable short-term efficacy, good tolerability, cost-effective nature, and low incidence of adverse effects.