Silencing of casein kinase 2 inhibits PKC‑induced cell invasion by targeting MMP‑9 in MCF‑7 cells

Abstract

Casein kinase 2 (CK2) is a serine/threonine protein kinase that has been considered to represent an important factor in mammary tumorigenesis. Increased expression of matrix metalloproteinase‑9 (MMP‑9) via nuclear factor‑κB (NF‑κB) activation has been demonstrated to promote breast cancer cell invasion. In the present study, the involvement of CK2 in protein kinase C (PKC) induced cell invasion in MCF‑7 breast cancer cells was investigated as well as the underlying molecular mechanisms. The mRNA and protein levels of MMP‑9 in MCF‑7 cells were investigated using reverse transcription‑quantitative polymerase chain reaction, western blot analyses and a zymography assay. Cell invasiveness was investigated using a Matrigel invasion assay, and it was revealed that small interfering RNA specific for CK2 suppressed PKC induced cell invasion by regulating MMP‑9 expression via activation of the p38 kinase/c‑Jun N‑terminal kinase/NF‑κB pathway. In addition, it was demonstrated that CK2 inhibitors [apigenin (20 µM), emodin (20 µM) or 2‑dimethylamino‑4,5,6,7‑tetrabromo‑1H‑benzimidazole (2 µM)] suppressed PKC induced cell invasion and MMP‑9 expression. The results of the present study suggested that CK2 is an important factor involved in the induction of MCF‑7 breast cancer cell invasion by PKC. Therefore, CK2 may represent novel candidates for therapy intended to inhibit invasion in breast cancer.

Apigenin upregulation of CD26/DPPIV on colon epithelial cells requires inhibition of casein kinase 2

“…In this work, we have shown that the apigenin upregulation of functional CD26/DPPIV at the cell surface of intestinal epithelial cells (a) is consistent across multiple well‐differentiated human cell lines, (b) is due to cellular redistribution rather than a change in expression, (c) may be reproduced by multiple inhibitors of CK2 kinase activity, (d) does not involve downregulation of CK2 protein, and (e) is abrogated by siRNA knockdown of available CK2. It is well established that apigenin can inhibit CK2 activity, and indeed, it is used experimentally as a CK2 inhibitor (Ahmad, Wang, & Ahmed, 2006; Jung, Kim, & Lee, 2014; Kim et al., 2018; Kroonen et al., 2012; Suhas et al., 2018). We conclude that the ability of apigenin to upregulate CD26/DPPIV involves inhibition of the kinase activity of CK2 and is dependent upon the presence of functional CK2 enzyme.…”

“…However, it is not certain that apigenin influences cellular behaviors, including regulation of interactions with the extracellular matrix, cellular contractility, and the levels of molecules including CD26/DPPIV (Kim et al., 2018; Lefort & Blay, 2011; Suhas et al., 2018), solely through inhibition of CK2. The effects of apigenin in cellular experimental systems are distinct from synthetic CK2 inhibitors such as CX‐4945 (Suhas et al., 2018).…”

“…Casein kinase 2 is elevated in proliferating tissues, both normal and neoplastic, and may contribute to the formation of certain neoplasias (Dubois et al., 2016; Pinna & Meggio, 1997; Sarno et al., 2002). In addition, it may contribute to more aggressive cancer behaviors such as invasion (Kim et al., 2018). There are suggestions that the suppression of CK2 might be a valid therapeutic intervention to reduce the invasive behavior of cancer cells (Kim et al., 2018).…”

“…In addition, it may contribute to more aggressive cancer behaviors such as invasion (Kim et al., 2018). There are suggestions that the suppression of CK2 might be a valid therapeutic intervention to reduce the invasive behavior of cancer cells (Kim et al., 2018). However, the protracted time course of the increase in cell surface CD26/DPPIV (24–48 hr) suggests that there are likely significant other events, most probably downstream of CK2, that participate in elevation of CD26/DPPIV.…”

“…CK2 is a tetrameric protein complex, composed of two catalytic subunits (α 42 kDa or α’ 38 kDa) and two regulatory subunits (β 28 kDa) in various combinations (Ahmad, Wang, Unger, Slaton, & Ahmed, 2008; Litchfield, 2003). CK2 is widely distributed in different cellular compartments and therefore able to influence multiple cellular processes and molecules (Kim et al., 2018; Litchfield, 2003; Suhas et al., 2018). We show here that apigenin's ability to upregulate CD26/DPPIV requires inhibition of this key cellular kinase casein, CK2.…”