Abstract
Recent studies provide compelling evidence that melanoma is initiated and maintained by a small population of malignant cells called cancer-initiating cells (CICs) that exhibit stem-cell-like properties. Observations that CICs have a distinct biology when compared to that of the bulk tumor cells and, importantly, are resistant to chemotherapies and radiation, suggest that CICs are involved in invasion, metastasis, and ultimately relapse. Lunasin, a bioactive peptide present in soybean, has both chemopreventive activity and chemotherapeutic activity against multiple cancer types. In this study, we tested the potential of Lunasin to specifically target CICs in melanoma tumor cell populations. In vitro studies using human melanoma cell lines showed that Lunasin treatment decreased the size of a subpopulation of melanoma cells expressing the surrogate CIC marker, Aldehyde Dehydrogenase, concomitant with a reduction in the ability to form colonies in soft agar assays, and reduced tumor growth in mouse xenografts. Similarly, Lunasin inhibited colony formation by isolated melanoma CICs in soft agar and reduced oncosphere formation in vitro and substantially inhibited tumor growth in mouse xenografts. Mechanistic studies revealed that Lunasin treatment of isolated melanoma CICs induced expression of the melanocyte-associated differentiation markers Tyrosinase and Microphthalmia-associated Transcription Factor concomitant with reduced expression of the stemness factor NANOG. These findings document for the first time that Lunasin has significant therapeutic activity against melanoma by specifically targeting melanoma CICs, and inducing a more differentiated, non-CIC phenotype. Thus, Lunasin may represent a novel therapeutic option for both chemoresistant and advanced metastatic melanoma management.
Highlights
Skin cancers account for nearly half of all diagnosed cancer cases in the United States and have increased in frequency over the last thirty years [1]
We found that Lunasin was effective over this dose range with human melanoma cell lines
These results establish that Lunasin inhibits anchorageindependent growth of melanoma in vitro and provides the first demonstration that Lunasin has therapeutic effects on human melanoma cells
Summary
Skin cancers account for nearly half of all diagnosed cancer cases in the United States and have increased in frequency over the last thirty years [1]. NCI’s Surveillance, Epidemiology, and End Results program estimates that cases of melanoma have nearly tripled in the past thirty years; the number of cases has increased from 7.9 (per 100,000) in 1975 to 22.7 in 2011, while the 5-year survival rate remains constant [2]. Recurrent disease is the major cause of morbidity and mortality associated with melanoma. Studies in preclinical models of carcinogenesis have shown that an enrichment of melanoma cancer initiating cells (CICs) is likely to occur after conventional chemotherapeutic regimens, implicating CICs in treatment resistance and cancer recurrence [3,4,5,6]. Successful elimination of CICs, along with the proliferating bulk www.impactjournals.com/oncotarget tumor melanoma cells could be an effective therapeutic strategy to achieve higher rates of complete remission, especially in patients with late stage melanoma
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