Reduction of Cytosolic p27Kip1 Inhibits Cancer Cell Motility, Survival, and Tumorigenicity

Abstract

We generated a p27Kip1 mutant (p27#NLS) that localized exclusively in cell cytosol. Expression of p27#NLS in MCF7 breast cancer cells down-regulated RhoA and increased motility, survival, and Akt levels without an effect on cell cycle distribution. RNA interference of p27 in U87 glioma cells, which express p27 predominantly in the cytoplasm, inhibited motility and survival. Conversely, knockdown of p27 in COS7 cells, with >95% nuclear p27 expression, accelerated proliferation but had no effect on motility or survival. U87 cells in which p27 had been eliminated by RNA interference exhibited lower Akt levels, shorter Akt turnover, and markedly impaired tumorigenicity in vivo. These xenografts were less invasive and exhibited increased apoptosis compared with p27-expressing tumors. Expression of cytosolic p27 in primary human breast carcinomas correlated linearly with Akt content as measured by immunohistochemistry. These data suggest that cytoplasmic p27 can exert oncogenic functions by modulating Akt stability, cell survival, and tumorigenicity. (Cancer Res 2006; 66(4): 2162-72)

Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis

“…Nuclear p27 inhibits cell cycle progression, whereas cytoplasmic p27 has been suggested to promote cell survival and motility (Assoian, 2004;Wu et al, 2006). Regulation of p27 localization is complex and may occur at multiple levels.…”

The E7 protein from human papillomavirus type 16 enhances keratinocyte migration in an Akt-dependent manner

“…Attenuation of the RhoA pathway leads to a decrease in both actin stress fiber and focal adhesion formation, allowing for an increase in migration (Nobes and Hall, 1999). Reduction of p27 expression has recently been directly linked to decreased invasiveness of tumor cells injected into mice (Wu et al, 2006a), implicating p27 directly as a modulator of invasive potential.…”

“…Although treatment of E7-expressing cells with LY294002 or AI4 did stabilize total p27 levels, the ratio of phosphorylated to total p27 was similar to that in DXRB-treated pBabe cells (Figure 3c). Cytoplasmic p27 has been demonstrated to increase the migration of cancer cells by an Akt-dependent mechanism and is associated with inhibition of the RhoA pathway (Besson et al, 2004;Vasko et al, 2004;Wu et al, 2006a). To evaluate whether RhoA activity itself was perturbed by E7 under conditions where cytoplasmic retention of p27 is observed, control and E7-expressing keratinocytes were treated with DXRB and RhoA activity was evaluated in a pulldown assay (Figure 4a).…”

Progesterone Stimulates Proliferation and Promotes Cytoplasmic Localization of the Cell Cycle Inhibitor p27 in Steroid Receptor Positive Breast Cancers

“…In the nucleus, p27 acts as a potent inhibitor of proliferation in the normal breast and breast cancer [13,14]. In the cytosol of breast cancer cells, p27 promotes cytoskeletal remodeling and cell motility [15,16]. Decreased nuclear and increased cytoplasmic expression of p27 is frequently observed in primary breast cancers and associated with poor clinical outcome [17,18].…”