Garkavtsev, Igor

Munn, Lance L.

Harvard University - DASH 

SLPI: a new target for stopping metastasisThe Harvard community has made thisarticle openly available.  Please share  howthis access benefits you. Your story mattersCitation Munn, Lance L., and Igor Garkavtsev. 2018. “SLPI: a new target forstopping metastasis.” Aging (Albany NY) 10 (1): 13-14. doi:10.18632/aging.101372. http://dx.doi.org/10.18632/aging.101372.Published Version doi:10.18632/aging.101372Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:35014922Terms of Use This article was downloaded from Harvard University’s DASHrepository, and is made available under the terms and conditionsapplicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA                                                                                               Secretory leukocyte protease inhibitor (SLPI) is known to be involved in the inhibition of inflammation, the modulation of immunological responses and the promotion of cell proliferation [1]. In cancer, increased SLPI expression can be detected in breast, lung, gastric and colorectal carcinomas.  Using antibody arrays that identify a panel of 350 murine and 500 human secreted proteins, we screened cancer cells to identify proteins that are highly expressed in metastatic compared to their non-metastatic counterparts. We found that SPLI was the only secreted protein increased in metastatic variants of both breast and colorectal cancer cells. Moreover, the SLPI level was associated with increased lung metastasis from orthotopically implanted tumors. These results suggest that high expression of SLPI in cancer cells may promote lung metastasis [2].   Next, we checked how SLPI expression levels correlate with the incidence of triple negative breast cancer (TNBC) metastasis in patients. We analyzed SLPI expression in TNBC because this subgroup represents the most aggressive breast cancer and still has the worst prognosis, despite advancements in modern thera-peutics. We found that both distant metastasis-free survival and overall survival were significantly worse in the TNBC patients who had higher SLPI expression in their tumors.  If SLPI is involved in tumor growth and metastasis, then pharmacological repression of SLPI should inhibit tumor expansion and dissemination. To identify potential small molecule blockers of SLPI, we used high-throughput screening to probe a library comprised of 60,000 chemically-diverse compounds. Candidate molecules that were able to reduce the SLPI expression by more than 90% but were not toxic to non-malignant cells were then tested in our mouse model of metastasis. We found that pharmacological repression of SLPI slows the growth of primary tumors and inhibits their dissemination to the lung [2]. These results suggest that SLPI is a new target for anti-metastatic therapies for breast and colon cancers.  What is a possible mechanism by which SLPI promotes metastasis? First, we found that SLPI physically inter-acts with and phosphorylates retinoblastoma (Rb) tumor suppressor protein. To determine whether SLPI inter-acts with Rb, we used protein extracts from two different cell lines and precipitated Rb complexes for SLPI detection. Our experiments confirmed that there is                                                                        Editorial        a physical association between these two proteins. This interaction was further confirmed by the reverse experiment in which anti-SLPI antibody was used for immunoprecipitation and anti-Rb antibody was used for detection. For further verification of this interaction, we used a standard mammalian two-hybrid approach and our results indicate that SLPI protein directly physically interacted with the Rb tumor suppressor. Moreover, we found that treatment with recombinant SLPI protein increased phosphorylation of Rb. On the other hand, treatment with the anti-SLPI compound decreased phosphorylation of Rb in breast cancer cells. Interes-tingly, it is known that phosphorylation of Rb leads to its release from FoxM1 binding [3] and initiates FoxM1 transcriptional activity. Indeed, we found that over-expression of SLPI leads to increased levels of known FoxM1 target proteins, such as cyclin B1, aurora kinase B and superoxide dismutase-2 (SOD-2). Moreover, we found that SLPI increases FoxM1 binding to FoxM1 target genes (Figure 1).                       Could SLPI overexpression cause cellular senescence through activation of the FoxM1? There is a body of literature showing that FoxM1-depletion is sufficient to induce cellular senescence in proliferating cells [4]. Activation of the FoxM1 gene suppresses reactive SLPI: a new target for stopping metastasis   Lance L. Munn and Igor Garkavtsev  www.aging‐us.com                      AGING 2018, Vol. 10, No. 1  www.aging‐us.com                     13                                                                                AGINGFigure 1.  Schematic representation of SLPI effect on theregulation  of  the  FoxM1  target  genes  and  subsequentmetastasis. SLPI activates  transcriptional  factor FoxM1, whichstimulates  expression  of  target  genes  involved  in  cell  division,cell  migration,  premetastatic  niche  formation,  epithelial–mesenchymal transition, senescence and metastasis.   oxygen species (ROS) and protects cancer cells from senescence [5]. Thus, overexpression of SLPI might prevent cellular senescence in cancer cells. On the other hand, FoxM1also regulates c-myc expression which has been shown to activate cellular senescence. Therefore, the effects of SLPI on cellular senescence warrants further investigation.  REFERENCES  1.   Zhang D, et al. J Biol Chem. 2002; 277:29999–30009. https://doi.org/10.1074/jbc.M203503200 2.   Kozin  SV,  et  al.  Oncotarget.  2017;  8:108292–302. https://doi.org/10.18632/oncotarget.22660 3.   Wierstra  I,  Alves  J.  Biol  Chem.  2006;  387:949–62. https://doi.org/10.1515/BC.2006.119 4.   Anders  L,  et  al.  Cancer  Cell.  2011;  20:620–34. https://doi.org/10.1016/j.ccr.2011.10.001 5.   Smirnov A, et al. Aging (Albany NY). 2016; 8:1384–97. https://doi.org/10.18632/aging.100988  Igor  Garkavstev:    Department  of  Radiation  Oncology, Massachusetts General Hospital, Harvard Medical  School, Boston, MA 02114, USA  Correspondence: Igor Garkavstev Email:  igorg@steele.mgh.harvard.edu Keywords: SLPI, FoxM1, anti‐metastatic compound Copyright: Munn and Garkavstev. This  is an open‐access article  distributed  under  the  terms  of  the  Creative Commons Attribution  License  (CC BY  3.0), which  permits unrestricted  use,  distribution,  and  reproduction  in  any medium,  provided  the  original  author  and  source  are credited  Received: January 12, 2018 Published: January 20, 2018   www.aging‐us.com                     14                                                                               AGING

SLPI: a new target for stopping metastasis

https://dash.harvard.edu/bitstream/1/35014922/1/5811255.pdf

SLPI: a new target for stopping metastasis

Abstract

Similar works

Full text

Available Versions

Harvard University - DASH