Maspin Regulates Different Signaling Pathways for Motility and Adhesion in Aggressive Breast Cancer Cells

Odero-Marah, Valerie; Khalkhali‐Ellis, Zhila; Chunthapong, Jirapat; Amir, Sumaira; Seftor, Richard E.B.; Seftor, Elisabeth A.; Hendrix, Mary J.C.

doi:10.4161/cbt.2.4.471

Cited by 70 publications

(76 citation statements)

References 46 publications

(35 reference statements)

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“…Maspin or G-helix peptide caused a cytoskeletal architecture indicative of a less motile phenotype; there was a reduction in the number of membrane spikes/lamelliopodia, and the actin filaments were increased in terms of length and thickness. This is in agreement with previous studies suggesting that maspin inhibits cell migration by inhibiting Rac1 and cdc42 (29,30).…”

Section: Discussionsupporting

confidence: 83%

G-helix of Maspin Mediates Effects on Cell Migration and Adhesion

Ravenhill¹,

Wagstaff²,

Edwards

et al. 2010

Journal of Biological Chemistry

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Maspin is a member of the serine protease inhibitor (serpin) superfamily that lacks protease inhibitory ability, although displaying tumor metastasis-suppressing activity resulting from its influence on cell migration, invasion, proliferation, apoptosis, and adhesion. The molecular mechanisms of these actions of maspin are as yet undefined. Here, we sought to identify critical functional motifs by the expression of maspin with point mutations at sites potentially involved in protein-protein interactions: the G ␣-helix (G-helix), an internal salt bridge or the P1 position of the reactive center loop. Our findings indicate that only mutations in the G-helix attenuated inhibition of cell migration by maspin and that this structural element is also involved in the effect of maspin on cell adhesion. The action of maspin on cell migration could be mimicked by a 15-mer G-helix peptide, indicating that the G-helix is both essential and sufficient for this effect. In addition, we provide evidence that the effects of the G-helix of maspin are dependent on ␤1 integrins. These data reveal that the major extracellular functions associated with the tumor suppressive action of maspin likely involve interactions in which the G-helix plays a key role.Maspin (SERPINB5) is a member of the serpin family of serine protease inhibitors that acts as a type II tumor metastasis suppressor, decreasing tumor growth and metastasis in vivo (1, 2) and invasion in vitro (3, 4). It is down-regulated in cancers including those of the breast (1) and prostate (5). Exogenous maspin decreases proliferation and increases cell adhesion in vitro (6). It inhibits angiogenesis in vivo (7) and causes apoptosis when expressed in endothelial cells (8). In addition, we have shown that maspin can inhibit the migration of vascular smooth muscle cells (VSMCs) 3 (9), which has potential ramifications for conditions resulting from vascular injury such as atherosclerosis.Maspin is expressed by epithelial cells and is essential for normal development because maspin-null mice die at the periimplantation stage due to a failure of early differentiation events, resulting from aberrant adhesion and cell migration (10). However, the mechanism of action of maspin remains largely unresolved. Although early evidence suggested that maspin was an inhibitory serpin able to block plasminogen activation by urokinase plasminogen activator and tissue-type plasminogen activator (11-13), we demonstrated that this was not the case in a number of conditions where the serpin PAI-1 was inhibitory (9). That maspin is a noninhibitory serpin is supported by crystal structure data revealing that its RCL does not correspond with those found in inhibitory serpins (14,15). It remains possible that maspin influences protease activity indirectly by noninhibitory interactions with the plasminogen activators (16, 17) and protection of matrix from degradation by cathepsin D (18).In common with the serpin PAI-2, maspin lacks an authentic signal sequence, but is found outside the cell as well as in t...

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Section: Discussionsupporting

confidence: 83%

G-helix of Maspin Mediates Effects on Cell Migration and Adhesion

Ravenhill¹,

Wagstaff²,

Edwards

et al. 2010

Journal of Biological Chemistry

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“…Maspin is a 42-kDa protein associated with various tumorrelated processes such as the inhibition of cell migration, cell invasion, angiogenesis, as well as improvement in cell adhesion and the induction of programmed cell death, thus classifying it as a tumor suppressor (8)(9)(10)(11)(12). Maspin expression has been observed in multiple tissues, e.g., epithelium of the breast, prostate, epidermis and lung (10,(22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

“…Investigations involving rMaspin as well as secreted Maspin may show various anti-tumor effects besides angiogenesis inhibition, such as restraint of tumor adhesion and motility, thereby also modulating invasion and metastasis. Urokinasetype plasminogen activator, urokinase-type plasminogen activator receptor and collagen type I and III were previously identified as extracellular targets that strengthen focal adhesion contacts (9,10). Among its biological functions, Maspin was found to induce apoptosis by regulating Bcl-2 family proteins and/or interacting with Hsp90 (11,12).…”

Section: Introductionmentioning

confidence: 99%

Maspin protein expression correlates with tumor progression in non-muscle invasive bladder cancer

Kramer

Waalkes²,

Hennenlotter³

et al. 2010

Oncology Letters

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Abstract. Maspin is a 42-kDa protein that belongs to the family of serine protease inhibitors. It is involved in various physiological processes. In cancer tissue, Maspin was found to influence angiogenesis, tumor growth, metastasis and the prognosis of tumor patients. This study was performed to analyze the involvement of Maspin in transitional cell carcinoma of the bladder as well as its prognostic impact in a large patient cohort. Specimens from 162 non-muscle invasive bladder cancer patients (pTa, 91; pT1, 71) treated by transurethral resection with a minimum 3-year follow-up (median 58.5 months) were included in the present investigation. Tissue microarrays were constructed, and the specimens were immunohistochemically stained for Maspin protein expression. Each tissue specimen was assessed on a staining scale ranging from 0 (no staining) to 300 (strong staining) and correlated with various clinicopathological parameters. Maspin protein expression predicted progression with a sensitivity of 95% and a specificity of 70% (p<0.001). In predicting recurrence, Maspin staining showed 52% sensitivity and 67% specificity (p<0.05). Kaplan-Meier analyses were performed, and a low Maspin protein expression was correlated with a higher incidence of tumor progression (p<0.0001). However, expression levels of Maspin protein did not distinguish between pTa and pT1 specimens. Multivariate analyses indicated Maspin expression as an independent factor for predicting progression (p<0.0001) and recurrence (p<0.05). The present results suggest that the Maspin protein expression is an independent prognostic indicator for predicting recurrence and progression to muscle invasive disease. This study further emphasizes a possible clinical role of this novel tumor suppressor gene in transitional cell carcinoma of the bladder.

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“…PAI-1 can reduce invasiveness in breast and ovarian cancer cells [27,28]. Maspin, a tumor-suppressing serpin (serine protease inhibitor) has been shown to suppress tumor cell invasion [29] and cell motility [30]. KAI1 is a known suppressor of tumor invasion and metastasis [31,32].…”

Section: Discussionmentioning

confidence: 99%