XIAP over-expression is an independent poor prognostic marker in Middle Eastern breast cancer and can be targeted to induce efficient apoptosis

Abstract

BackgroundBreast cancer is the most common cancer in females and is ranked second in cancer-related deaths all over the world in women. Despite improvement in diagnosis, the survival rate of this disease has still not improved. X-linked Inhibitor of Apoptosis (XIAP) has been shown to be over-expressed in various cancers leading to poor overall survival. However, the role of XIAP in breast cancer from Middle Eastern region has not been fully explored.MethodsWe examined the expression of XIAP in more than 1000 Middle Eastern breast cancer cases by immunohistochemistry. Apoptosis was measured by flow cytometry. Protein expression was determined by western blotting. Finally, in vivo studies were performed on nude mice following xenografting and treatment with inhibitors.ResultsXIAP was found to be over-expressed in 29.5% of cases and directly associated with clinical parameters such as tumor size, extra nodal extension, triple negative breast cancer and poorly differentiated breast cancer subtype. In addition, XIAP over-expression was also significantly associated with PI3-kinase pathway protein; p-AKT, proliferative marker; Ki-67 and anti-apoptotic marker; PARP. XIAP over-expression in our cohort of breast cancer was an independent poor prognostic marker in multivariate analysis. Next, we investigated inhibition of XIAP using a specific inhibitor; embelin and found that embelin treatment led to inhibition of cell viability and induction of apoptosis in breast cancer cells. Finally, breast cancer cells treated with combination of embelin and PI3-kinase inhibitor; LY294002 synergistically induced apoptosis and caused tumor growth regression in vivo.ConclusionThese data suggest that XIAP may be playing an important role in the pathogenesis of breast cancer and can be therapeutically targeted either alone or in combination with PI3-kinase inhibition to induce efficient apoptosis in breast cancer cells.Electronic supplementary materialThe online version of this article (10.1186/s12885-017-3627-4) contains supplementary material, which is available to authorized users.

Embelin impact on paraquat‐induced lung injury through suppressing oxidative stress, inflammatory cascade, and MAPK/NF‐κB signaling pathway

“…Embelin decreased the paraquat‐prompted OS in our model, which is in concurrence with its antioxidant and anti‐inflammation effects. [ 11,26,27 ] ROS excessively generated inside the lungs can prompt OS, bringing about lung damage; moreover, it can activate inflammation of the airways, in this way adding to the pathogenesis of the respiratory disease. A few inflammatory cytokines (TNF‐α, IL‐1β, and IL‐6), as well as the transcription factor NF‐κB, assume significant roles in the advancement of lung inflammation.…”

Prognostic value of XIAP and survivin expression in locally advanced breast cancer patients treated with anthracycline-based neoadjuvant chemotherapy

“…In contrast, Xu et al did not observe any significant correlation between high XIAP expression and breast cancer stage, as a high cytosolic fraction of this protein was detected in 18% of patients in stage II and in 12% of patients in stage III [20]. In a large cohort presented by Hussain et al XIAP protein was overexpressed in 29.5% of 1009 breast cancer patients, irrespective of the tumour stage and lymph node involvement [18].…”

“…It contains three BIR domains and is the only IAP family member to inhibit caspases through a direct physical interaction [14]. High expression of XIAP has been found to be associated with resistance to chemotherapy in various malignancies and a few studies have presented its clinical role in breast cancer patients [13,[15][16][17][18][19][20][21].…”

Long‐term exposure to extremely low‐dose of nicotine and 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) induce non‐malignant breast epithelial cell transformation through activation of the a9‐nicotinic acetylcholine receptor‐mediated signaling pathway

“…Furthermore, FAK a migration marker and PI3K/AKT pathway which is considered as the major intracellular signaling pathway that plays a significant role in tumor growth and cellular proliferation, were also significantly increased upon exposure to combined carcinogens starting from cycle 15. Moreover, higher expression of XIAP, which may plays an important role in breast cancer pathogenesis by inhibiting apoptosis, and p‐S6K, a 70‐kDa ribosomal protein S6 kinase, which is a master regulator of cell growth and proliferation and decrease the expression of a well‐known apoptotic BAX protein, have been observed (Figure C,D). Altogether, these results indicate that even very low doses of carcinogens can increase cell growth and cell proliferation in an exposure‐dependent manner.…”