Dual Roles of Ascidian Chondromodulin-1: Promoting Cell Proliferation Whilst Suppressing the Growth of Tumor Cells

Abstract

Chondromodulin-1 (ChM-1) is an extracellular matrix protein that plays crucial roles in tumor cell growth and angiogenesis in vertebrates and humans. ChM-1 is highly expressed in the invertebrate Ciona savignyi, a marine ascidian chosen as a model. The effect of the recombinant Ciona mature ChM-1 peptide (Cs-mChM-1) on cell proliferation, migration and angiogenesis was evaluated on cultured cells. The results revealed that low concentrations of Cs-mChM-1 (12.5 nM) promoted osteoblastic cell (MC3T3-E1) growth and protected cells from H2O2-induced damage. However, a higher concentration of Cs-mChM-1 (i.e., 500 nM) not only suppressed both growth and migration of tumor cells, including human cervical cancer (HeLa) cells and human neuroblastoma (SH-SY5Y) cells, but also significantly inhibited proliferation and angiogenesis of human umbilical vein endothelial cells (HUVECs). The expression levels of cyclinD1 and mitogen-activated protein kinase 1 (MAPK1) were slightly increased in Cs-mChM-1 treated MC3T3-E1 cells, whereas these genes decreased in treated HeLa cells, SH-SY5Y cells and HUVECs. This result indicates that Cs-mChM-1 modifies cell behavior by regulating cell cycle and cell adhesion. Thus, the present results reveal that recombinant peptides of ChM-1 from invertebrates can play a dual role in cell proliferation and migration of different cell types. The inhibition effects on tumor cell growth and angiogenesis indicate potential pharmaceutical applications for recombinant Cs-mChM-1.

Chondromodulin-1 in health, osteoarthritis, cancer, and heart disease

“…Chm-1 expression was also detected in lacuna cells and neoplastic myoepithelial cells during the pathogenesis of pleomorphic adenoma, which is indicative of its involvement in the hypo-vascularity and chondroid formation of pleomorphic adenoma [48]. At the cellular level, Chm-1 appears to be capable of exhibiting a dual role by promoting cell proliferation and suppressing the growth of tumour cells in a dose-dependent relationship [49]. Low concentrations of Chm-1 appear to promote osteoblastic-cell growth, whereas higher concentrations of Chm-1 suppressed the growth and migration of tumour cells, such as human cervical cancer (HeLa) cells and human neuroblastoma (SH-SY5Y) cells, and inhibited the proliferation and angiogenesis of human umbilical vein endothelial cells (HUVECs) [49].…”

“…At the cellular level, Chm-1 appears to be capable of exhibiting a dual role by promoting cell proliferation and suppressing the growth of tumour cells in a dose-dependent relationship [49]. Low concentrations of Chm-1 appear to promote osteoblastic-cell growth, whereas higher concentrations of Chm-1 suppressed the growth and migration of tumour cells, such as human cervical cancer (HeLa) cells and human neuroblastoma (SH-SY5Y) cells, and inhibited the proliferation and angiogenesis of human umbilical vein endothelial cells (HUVECs) [49]. Reports suggest that the anti-angiogenic properties of Chm-1 may contribute to the inhibitory effect of tumour progression [50, 51].…”

Origins and Bioactivities of Natural Compounds Derived from Marine Ascidians and Their Symbionts

“…In human neuroblastoma (SHSY5Y) cells, human cervical cancer (HeLa) cells, and human umbilical vein endothelial cells (HUVECs), Cs-mChM-1 suppresses cell proliferation and inhibits angiogenesis of HUVECs. Further experiments revealed that Cs-mChM-1 modifies cell behavior through regulating the cell cycle and cell adhesion [58]. These results suggest that Cs-mChM-1 is a potential antioxidant and antitumor agent.…”

“…ChM-1, a 25 kDa glycoprotein originally isolated from fetal bovine cartilage, could be converted to a 12 kDa mature peptide at the C-terminal RERR amino acid cleavage site and subsequently secreted to the extracellular matrix [57]. Recently, ChM-1 was identified from the invertebrate urochordate ascidian Ciona savignyi [58]. As an invertebrate animal without cartilage and vascellum, the role of the highly expressed ChM-1 indicated its novel function.…”