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Galadari: Cystatin SA – a molecule with novel anticancer properties based on the inhibition of acid ceramidase

For the past few decades, the main focus of research in the field of proteases and their role in cancer progression has been on matrix metalloproteases and serine proteases. Cysteine cathepsins (CCs), a family of lysosomal proteases, and their endogenous inhibitors, cystatins, received little attention until the late 1990s. CCs are implicated in a number of tumorigenic processes, such as tumour growth, invasion and metastasis.1 With the failure of serine proteases and metalloprotease inhibitors in clinical trials, CCs have now emerged as targets for anticancer therapies.1

The human CCs comprise 11 members, namely CC B, C, F, H, K, L, O, S, V, W and X. The cystatins are grouped into five families: stefins, cystatins, latexins, fetuins and kininogens. These groups have physiological2 and pathological significance.3 In recent years, several reports have demonstrated the involvement of CCs in cancer progression.4 Up-regulation of CCs was reported in breast, brain, lung and gastrointestinal cancers, as well as colorectal cancer and melanoma.4 Several approaches have been developed to block CC activity. These include small-molecule inhibitors, antibodies and increased production of cystatins.1 Cystatins are reversible, competitive and endogenous inhibitors of CCs. Various reports have suggested that there exists an inverse correlation between the stage of tumour progression and the levels of cystatins.5 The tumour-suppressing properties of cystatin family members, such as stefin A, stefin B, fetuin B, cystatin M and cystatin C, have been demonstrated in several studies.6 Their antitumour activity is not attributed solely to the inhibition of CCs. For instance, cystatin C has recently been described as a tumour growth factor β-receptor antagonist.7

In a recent research article, Eliyahu et al.8 demonstrated a new mechanism of cystatin action that could be targeted for use in anticancer therapy. Using co-immunoprecipitation and co-localization techniques in two different cell lines – one (SK-MEL; human skin melanoma) with high and the other (HEK293T/17) with low endogenous acid ceramidase (AC; N-acylsphingosine deacylase; EC 3.5.1.23) expression – the authors elegantly demonstrated that cystatin SA (cysSA) is a potent physiological inhibitor of AC. This enzyme is very important in regulating the conversion of ceramide (Cer) to sphingosine-1-phosphate (S1P). Ceramide is a proapoptotic (tumour-suppressing) lipid involved in apoptosis, autophagy and growth inhibition. S1P is an antiapoptotic (tumour-promoting) lipid with roles in angiogenesis, cell survival and proliferation. The balance between Cer and S1P is known as the Cer–S1P rheostat, and is critical in determining whether a cell will die or proliferate. Owing to cysSA's ability to regulate the Cer-S1P rheostat, the inhibition of the AC enzyme has emerged as an attractive target for the treatment of cancer.

The involvement of AC in cancer development has been demonstrated in several studies, which report its overexpression in a wide variety of cancers including those of the prostate, head and neck, as well as melanoma and glioblastoma.9,10 Similarly, when AC was inhibited using N-oleoylethanolamine, an increase in ceramide formation and enhanced apoptosis was observed in glioma, fibrosarcoma and hepatoma cells.10 Another inhibitor of AC, B13, has also been shown to induce apoptosis in prostate and colon cancers and adenocarcinoma.11 Using recent advances in ribonucleic acid (RNA) interference technology, knockout of AC in L929 cells resulted in a significant accumulation of ceramide, and the induction of apoptosis.12 Furthermore, AC overexpression has been reported to confer resistance to common proapoptotic agents, such as tumour necrosis factors, doxorubicin, etoposide, cisplatin and gemcitabine.13,14 Thus, an inverse correlation appears to exist between AC activity and cell death.

These findings suggest that AC inhibition, alone or in combination with other anticancer treatments, may serve as a useful target for cancer therapy.14 This highlights the need for identification and synthesis of more specific potent inhibitors of AC. CysSA, identified by Eliyahu et al.8 as a novel endogenous inhibitor for AC, may be a candidate. These authors also predicted the mechanism of interaction between cysSA and AC using laboratory techniques and computer modelling. The authors demonstrated that the interaction between AC and cysSA occurs via a non-competitive inhibition mechanism, which may be facilitated by the AC-like domain in cysSA. They were also able to synthesize two small peptides based on the cysSA sequence, both of which were found to be effective inhibitors of AC in vitro.

In summary, cysSA is a possible therapeutic agent for the treatment of cancer, either alone or in combination with other drugs. However, longer-term studies are required to assess the full usefulness of this novel therapeutic weapon. In the future, we can also expect the use of cysSA-based peptides or inducers of cysSA for the treatment of various types of cancers.

References

1. 

Palermo C, Joyce JA. Cysteine cathepsin proteases as pharmacological targets in cancer. Trends Pharmacol Sci 2008; 29:22–8. http://dx.doi.org/10.1016/j.tips.2007.10.011

2. 

Reinheckel T, Deussing J, Roth W, Peters C. Towards specific functions of lysosomal cysteine peptidases: phenotypes of mice deficient for cathepsin B or cathepsin L. Biol Chem 2001; 382:735–41. http://dx.doi.org/10.1515/BC.2001.089

3. 

Yasuda Y, Kaleta J, Bromme D. The role of cathepsins in osteoporosis and arthritis: rationale for the design of new therapeutics. Adv Drug Deliv Rev 2005; 57:973–93. http://dx.doi.org/10.1016/j.addr.2004.12.013

4. 

Jedeszko C, Sloane BF. Cysteine cathepsins in human cancer. Biol Chem 2004; 385:1017–27. http://dx.doi.org/10.1515/BC.2004.132

5. 

Korolenko TA, Poteryaeva ON, Falameeva OV, Levina OA. Cystein proteinase inhibitor stefin A as an indicator of efficiency of tumor treatment in mice. Bull Exp Biol Med 2003; 136:46–8. http://dx.doi.org/10.1023/A:1026084712399

6. 

Keppler D. Towards novel anti-cancer strategies based on cystatin function. Cancer Lett 2006; 235:159–76. http://dx.doi.org/10.1016/j.canlet.2005.04.001

7. 

Sokol JP, Schiemann WP. Cystatin C antagonizes transforming growth factor beta signaling in normal and cancer cells. Mol Cancer Res 2004; 2:183–95.

8. 

Eliyahu E, Shtraizent N, He X, Chen D, Shalgi R, Schuchman EH. Identification of cystatin SA as a novel inhibitor of acid ceramidase. J Biol Chem 2011; 286:35624–33. http://dx.doi.org/10.1074/jbc.M111.260372

9. 

Norris JS, Bielawska A, Day T, et al. Combined therapeutic use of AdGFPFasL and small molecule inhibitors of ceramide metabolism in prostate and head and neck cancers: a status report. Cancer Gene Ther 2006; 13:1045–51. http://dx.doi.org/10.1038/sj.cgt.7700965

10. 

Hara S, Nakashima S, Kiyono T, et al. p53-Independent ceramide formation in human glioma cells during gamma-radiation-induced apoptosis. Cell Death Differ 2004; 11:853–61. http://dx.doi.org/10.1038/sj.cdd.4401428

11. 

Park JH, Schuchman EH. Acid ceramidase and human disease. Biochim Biophys Acta 2006; 1758:2133–8.

12. 

Zeidan YH, Pettus BJ, Elojeimy S, et al. Acid ceramidase but not acid sphingomyelinase is required for tumor necrosis factor-{alpha}-induced PGE2 production. J Biol Chem 2006; 281:24695–703. http://dx.doi.org/10.1074/jbc.M604713200

13. 

Strelow A, Bernardo K, Adam-Klages S, et al. Overexpression of acid ceramidase protects from tumor necrosis factor-induced cell death. J Exp Med 2000; 192:601–12. http://dx.doi.org/10.1084/jem.192.5.601

14. 

Morales A, Paris R, Villanueva A, Llacuna L, Garcia-Ruiz C, Fernandez-Checa JC. Pharmacological inhibition or small interfering RNA targeting acid ceramidase sensitizes hepatoma cells to chemotherapy and reduces tumor growth in vivo. Oncogene 2007; 26:905–16. http://dx.doi.org/10.1038/sj.onc.1209834





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