Knockdown of metallopanstimulin‐1 inhibits NF‐κB signaling at different levels: The role of apoptosis induction of gastric cancer cells

Abstract

The ribosomal protein S27 (metallopanstimulin-1, MPS-1) has been reported to be a multifunctional protein, with increased expression in a number of cancers. We reported previously that MPS-1 was highly expressed in human gastric cancer. Knockdown of MPS-1 led to spontaneous apoptosis and repressed proliferation of human gastric cancer cells in vitro and in vivo. However, how does MPS-1 regulate these processes is unclear. Here we performed microarray and pathway analyses to investigate possible pathways involved in MPS-1 knockdown-induced apoptosis in gastric cancer cells. Our results showed that knockdown of MPS-1 inhibited NF-jB activity by reducing phosphorylation of p65 at Ser536 and IjBa at Ser32, inhibiting NF-jB nuclear translocation, and down-regulating its DNA binding activity. Furthermore, data-mining the Gene-RegulatoryNetwork revealed that growth arrest DNA damage inducible gene 45b (Gadd45b), a direct NF-jB target gene, played a critical role in MPS-1 knockdown-induced apoptosis. Over-expression of Gadd45b inhibited MPS-1 knockdown-induced apoptosis via inhibition of JNK phosphorylation. Taken together, these data revealed a novel pathway, the MPS-1/NF-jB/Gadd45b signal pathway, played an important role in MPS-1 knockdown-induced apoptosis of gastric cancer cells. This study sheds new light on the role of MPS-1/NF-jB in apoptosis and the possible use of MPS-1 targeting strategy in the treatment of gastric cancer.Gastric cancer is one of the most common cancers worldwide and it has the second highest mortality rate among all cancers.1 Although combination therapies are commonly used, the outcome of gastric cancer remains poor as the precise molecular events responsible for its generation and progression are still unknown. 2 In our previous studies, we used serological analysis of recombinant cDNA expression libraries (SEREX) to define new gastric cancer-related antigens and we successfully identified an array of relevant proteins, including metallopanstimulin-1 (MPS-1), 3 plant homeodomain finger 10 (PHF10) 4 and frizzled-related protein (FRZB). 5The MPS-1 protein, also known as ribosomal protein S27 (RPS27), is a component of the 40S subunit of the ribosome and belongs to the S27E family of ribosomal proteins.6 Being a zinc finger protein of C4 type, MPS-1 locates both in the cytoplasm and the nucleus. Previous studies demonstrated that MPS-1 is highly expressed in many types of malignant tumors and might be involved in the malignant progression. [7][8][9][10] In addition, the level of MPS-1 protein was found to be elevated in the sera of patients with various types of cancers and it was studied as a tumor marker or tumor-associated antigen;11,12 yet, the role of MPS-1 in tumorigenesis is unclear. We reported previously that the expression of MPS-1 was significantly higher in gastric cancer cells than their normal counterparts. Down-regulation of MPS-1 by shRNAs in gastric cancer cell line SGC-7901 increased spontaneous apoptosis and inhibited the tumor growth in vitro and in vivo.13 However, how do...

WITHDRAWN: Metformin antagonizes MPS-1-mediated IL-6/Stat3 signaling in ovarian cancer cells: possible mechanisms of stemness and angiogenesis inhibition

“…Previous studies on MPS-1 were limited to tumor markers identification and its over-expression was observed in different kinds of cancers which may be involved in tumorigenesis [5]. IL-6/STAT3 signaling pathway has been reported to stimulate cell proliferation and migration and protect tumor cells against druginduced apoptosis [15].…”

“…In addition, Knockdown or downregulation of MPS-1 also has been shown to induce spontaneous apoptosis and inhibit proliferation of human gastric cancer cells in vitro and in vivo [5]. Interleukin-6 (IL-6), a proinflammatory cytokine released by cancer associated fibroblasts, has been correlated with the invasive and metastatic behavior of ovarian cancer cells.…”

The role of ribosomal proteins in the regulation of cell proliferation, tumorigenesis, and genomic integrity

“…Activated p53 then transactivates its downstream targets to induce growth arrest and apoptosis to block tumorigenesis. (Adilakshmi and Laine, 2002;Bai et al, 2014;Barlow et al, 2010a;He and Sun, 2007;Jang et al, 2012a;Jeon et al, 2008;Khanna et al, 2003;Li et al, 2010;Naora et al, 1998;Neumann and Krawinkel, 1997;Russo et al, 2013;Takagi et al, 2005;Wu et al, 2012;Yang et al, 2012;Zhu et al, 2009) Cell cycle S3, S5, S6, S7, S14, S15, S19, S20, S25, S26, S27, S27L, S27a, L3, L5, L6, L7, L11, L13, L23, L26, L31, L34, L37, L41 (Cui et al, 2014;Daftuar et al, 2013;Dai et al, , 2007bGao et al, 2013;Gou et al, 2010;Iadevaia et al, 2010;Kobayashi et al, 2006;Maruyama et al, 2014;Matragkou et al, 2008;Moorthamer and Chaudhuri, 1999;Neumann and Krawinkel, 1997;Russo et al, 2013;Sun et al, 2011;Takagi et al, 2005;Wang et al, 2011a;Wanzel et al, 2008;Xiong et al, 2011;Zhang et al, 2013Zhang et al, , 2015Zhou et al, 2013a) Cell proliferation S6, S9, S13, S14, S15a, S24, S27, L6, L8, L11, L15, L17, L26, L29, L31, L34, L36a (Dai et al, 2007a;Gou et al, 2010Kim et al, 2004;Li et al, 2010…”

“…Both L3 and L7 were also reported to induce apoptosis (Neumann and Krawinkel, 1997;Russo et al, 2013). In contrast, some RPs, such as S27 and L23, exhibit anti-apoptotic activity Yang et al, 2012). S27 (also known as metallopanstimulin-1, MPS-1) was highly expressed in many human cancers and its knock-down induced apoptosis through the inhibition of NF-κB activity by reducing phosphorylation of p65 at Ser536 and IκBα at Ser32 .…”

RPS27 (ribosomal protein S27)

“…Furthermore, stabilization of mutant p53 levels associated with RPS27 abundance could provide malignant cells with a growth advantage (Xiong et al, 2011). RPS27 knockdown was found to enhance spontaneous apoptosis of tumor cells via caspase-3 activation (Wang et al, 2006;Yang et al, 2011). HNSCC: some have questioned if RPS27 overexpression is the cause or result of cancer.…”