214P - Versican G3 domain promotes myeloma cell proliferation, migration and invasion via activation of FAK/STAT3 signaling

Background

The rising incidence and mortality due to multiple myeloma (MM) is an alarming concern worldwide. Though, available chemotherapeutics possess the potential for treatment of MM, however, refractory and relapse condition in patients along with the associated side effects prompts to identify an effective treatment modality. Previously, our group reported myeloma-promoting effect of a chondroitin sulfate proteoglycan, Versican and showcased as an important target but the domain of this proteoglycan responsible for myeloma pathogenesis was not known. Hence, we assessed the effect of C-terminal domain (or G3 domain) of Versican in myeloma pathogenesis in vitro.

Methods

C-terminal (or G3) domain of Versican pertaining to 266 amino acids was commercially synthesized. This domain was supplemented in culture medium of myeloma cells (RPMI8226 & U266) at varied concentrations ranging from 100pM to 2000pM. Following treatment, effect of Versican C-terminal domain was investigated on cell proliferation, apoptosis, migration & invasion by suitable cell-based assays. Furthermore, the downstream signaling pathways affected by G3 domain of versican was identified by western blotting.

Results

The presence of Versican G3 domain in the extracellular milieu of cultured cells resulted in enhanced proliferation of myeloma cells. In addition, cell apoptosis was reduced while migratory and invading ability of myeloma cells potentiated when C-terminal domain of versican was added in the culture medium. All these effects of versican C-terminal domain were obtained due to the activation of FAK and STAT3 signaling cascades in multiple myeloma cells.

Conclusions

G3 (or C-terminal) portion of versican induced myeloma cell proliferation, migration and invasion of myeloma cells with simultaneous reduction in cell apoptosis via FAK/STAT3 signaling mechanism. These findings suggest the role of versican G3 domain as a plausible therapeutic target which could be tested further in myeloma xenograft models.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

All India Institute of Medical Sciences (AIIMS), New Delhi, India.

Funding

All India Institute of Medical Sciences (AIIMS), New Delhi, India.

Disclosure

All authors have declared no conflicts of interest.