Sperm associated antigen 9 (SPAG9) a promising therapeutic target of ovarian carcinoma

Abstract

SPAG9 is a novel tumor associated antigen, expressed in variety of malignancies. However, its role in ovarian cancer remains unexplored. SPAG9 expression was validated in ovarian cancer cells by real time PCR and Western blot. SPAG9 involvement in cell cycle, DNA damage, apoptosis, paclitaxel sensitivity and epithelial- mesenchymal transition (EMT) was investigated employing RNA interference approach. Combinatorial effect of SPAG9 ablation and paclitaxel treatment was evaluated in in vitro. Quantitative PCR and Western blot analysis revealed SPAG9 expression in A10, SKOV-3 and Caov3 compared to normal ovarian epithelial cells. SPAG9 ablation resulted in reduced cellular proliferation, colony forming ability and enhanced cytotoxicity of chemotherapeutic agent paclitaxel. Effect of ablation of SPAG9 on cell cycle revealed S phase arrest and showed decreased expression of CDK1, CDK2, CDK4, CDK6, cyclin B1, cyclin D1, cyclin E and increased expression of tumor suppressor p21. Ablation of SPAG9 also resulted in increased apoptosis with increased expression of various pro- apoptotic molecules including BAD, BID, PUMA, caspase 3, caspase 7, caspase 8 and cytochrome C. Decreased expression of mesenchymal markers and increased expression of epithelial markers was found in SPAG9 ablated cells. Combinatorial effect of SPAG9 ablation and paclitaxel treatment was evaluated in in vitro assays which showed that ablation of SPAG9 resulted in increased paclitaxel sensitivity and caused enhanced cell death. In vivo ovarian cancer xenograft studies showed that ablation of SPAG9 resulted in significant reduction in tumor growth. Present study revealed therapeutic potential of SPAG9 in ovarian cancer.

Knockdown of A-kinase anchor protein 4 inhibits proliferation of triple-negative breast cancer cells in vitro and in vivo

“…Our recent study also revealed similar observation that showed increased cytotoxicity with paclitaxel in SPAG9 knockdown ovarian cancer cells. 30 Yet another study also showed that knockdown of CDK11 increased ovarian cancer cell death when treated along with paclitaxel. 37 However, increased paclitaxel cytotoxicity in AKAP4 downregulated TNBC cells requires in-depth understanding of molecular pathways and warrants further studies.…”

“…Combinatorial effect of AKAP4 shRNA and paclitaxel in different combinations was examined in MDA-MB-231 cells as described earlier. 30 Combination index (CI) values were assessed using CompuSyn 1.01 software (ComboSyn, Inc., Paramus, NJ, USA). The experiments were carried out in triplicates three independent times.…”

The Role of Epithelial-to-Mesenchymal Plasticity in Ovarian Cancer Progression and Therapy Resistance

“…In line with this, reduced proliferation mediated by p21, which drives G1 growth arrest, led to resistance to taxanes in eight ovarian cancer cell lines that showed an EMT-signature. Indeed, it is well known that proliferating cells respond better than quiescent cells to taxanes [122].…”

ARAP1 is an independent prognostic biomarker in older women with ovarian high-grade serous adenocarcinoma receiving first-line platinum-based antineoplastic therapy

“…SPAG9 belongs to the cancer testis antigen (CTA) family, which represents a unique class of tumor antigens with normal expression in the testis and aberrant expression in various malignancies [34]. It has been identified as a promising biomarker for early detection and a therapeutic target for several cancers, including ovarian, cervix, breast and renal cell carcinoma [35][36][37][38][39]. MGST is a membrane protein localized to the endoplasmic reticulum and outer mitochondrial membrane, where it serves a protective function.…”