The Calpain/Calpastatin System Has Opposing Roles in Growth and Metastatic Dissemination of Melanoma

Abstract

Conventional calpains are ubiquitous cysteine proteases whose activity is promoted by calcium signaling and specifically limited by calpastatin. Calpain expression has been shown to be increased in human malignant cells, but the contribution of the calpain/calpastatin system in tumorigenesis remains unclear. It may play an important role in tumor cells themselves (cell growth, migration, and a contrario cell death) and/or in tumor niche (tissue infiltration by immune cells, neo-angiogenesis). In this study, we have used a mouse model of melanoma as a tool to gain further understanding of the role of calpains in tumor progression. To determine the respective importance of each target, we overexpressed calpastatin in tumor and/or host in isolation. Our data demonstrate that calpain inhibition in both tumor and host blunts tumor growth, while paradoxically increasing metastatic dissemination to regional lymph nodes. Specifically, calpain inhibition in melanoma cells limits tumor growth in vitro and in vivo but increases dissemination by amplifying cell resistance to apoptosis and accelerating migration process. Meanwhile, calpain inhibition restricted to host cells blunts tumor infiltration by immune cells and angiogenesis required for antitumor immunity, allowing tumor cells to escape tumor niche and disseminate. The development of highly specific calpain inhibitors with potential medical applications in cancer should take into account the opposing roles of the calpain/calpastatin system in initial tumor growth and subsequent metastatic dissemination.

Calpastatin Counteracts Pathological Angiogenesis by Inhibiting Suppressor of Cytokine Signaling 3 Degradation in Vascular Endothelial Cells

“…[25][26][27][28][29] Indeed, expression levels of μ-calpain correlate with malignancy in renal cell carcinoma and invasiveness in hepatocellular carcinoma. 28,29 Systemic overexpression of CAST and pharmacological intervention against systemic calpain systems reportedly ameliorate allograft tumors 30 and OIR, 14 respectively; nevertheless, the mechanism underlying calpain system contribution to such diseases is poorly understood. Our present data suggested that targeting EC calpain systems eliminates VEGF-C deposition in the cells, and it is sufficient for suppressing allograft tumors and OIR (Figures 2 and 3).…”

Calpain-2 Inhibitor Therapy Reduces Murine Colitis and Colitis-associated Cancer

“…35 Calpain expression has been correlated with chemotherapeutic resistance in colorectal cancer, esophageal cancer, and melanoma. 21,36,37 This resistance has been specifically correlated with calpain-2 activity. In melanoma, the correlation has been extended to survival outcomes with tumors expressing high levels of calpain-2 resulting in shorter survival for patients.…”

“…In melanoma, the correlation has been extended to survival outcomes with tumors expressing high levels of calpain-2 resulting in shorter survival for patients. 37,38 Importantly, calpain proteolytic activity has been shown to increase NFκB signaling in melanoma cancer cells and treatment with calpain inhibitor was able to attenuate this signaling in cisplatin resistant cells. 38 Other researchers have demonstrated a correlation between calpain expression and drug resistant esophageal cancer.…”

Effects of calpain inhibitor on the apoptosis of hepatic stellate cells induced by calcium ionophore A23187

“…This compound can also cause an ERS response in some cells, but this phenomenon has not yet been examined in HSCs. Calpain inhibitors are tetrapeptide acetal protease inhibitors that behave similarly to intracellular endogenous calpain inhibitory proteins by recognizing and specifically binding to conformational features of calpain associated with Ca 2+ binding, thus reducing calpain activity . In the present study, we treated TGF‐β1‐induced HSCs with calcium ionophore A23187 and calpain inhibitor to explore the effect on apoptosis resulting from ERS pathway activation.…”