Cystatin SN inhibits auranofin-induced cell death by autophagic induction and ROS regulation via glutathione reductase activity in colorectal cancer

Abstract

Cystatin SN (CST1) is a specific inhibitor belonging to the cystatin superfamily that controls the proteolytic activities of cysteine proteases such as cathepsins. Our previous study showed that high CST1 expression enhances tumor metastasis and invasiveness in colorectal cancer. Recently, auranofin (AF), a gold(I)-containing thioredoxin reductase 1 (TrxR1) inhibitor, has been used clinically to treat rheumatoid arthritis. AF is a proteasome-associated deubiquitinase inhibitor and can act as an anti-tumor agent. In this study, we investigated whether CST1 expression induces autophagy and tumor cell survival. We also investigated the therapeutic effects of AF as an anti-tumor agent in colorectal cancer (CRC) cells. We found that CRC cells expressing high levels of CST1 undergo increased autophagy and exhibit chemotherapeutic resistance to AF-induced cell death, while those expressing low levels of CST1 are sensitive to AF. We also observed that knockdown of CST1 in high-CST1 CRC cells using CST1-specific small interfering RNAs attenuated autophagic activation and restored AF-induced cell mortality. Conversely, the overexpression of CST1 increased autophagy and viability in cells expressing low levels of CST1. Interestingly, high expression of CST1 attenuates AF-induced cell death by inhibiting intracellular reactive oxygen species (ROS) generation, as demonstrated by the fact that the blockage of ROS production reversed AF-induced cell death in CRC cells. In addition, upregulation of CST1 expression increased cellular glutathione reductase (GR) activity, reducing the cellular redox state and inducing autophagy in AF-treated CRC cells. These results suggest that high CST1 expression may be involved in autophagic induction and protects from AF-induced cell death by inhibition of ROS generation through the regulation of GR activity.

Differentially expressed lncRNAs and mRNAs identified by NGS analysis in colorectal cancer patients

“…The expression of TCN1, MMP7, and MAGE‐A3 was increased in CRC tissues. High CST1 expression enhances tumor metastasis and invasiveness in CRC . SLCO1B3 was validated, and its protein expression was closely related to expression of tumor proximal location and mismatch repair genes .…”

“…High CST1 expression enhances tumor metastasis and invasiveness in CRC. 21 SLCO1B3 was validated, and its protein expression was closely related to expression of tumor proximal location and mismatch repair genes. 22 KRT6B might be involved in the development, progression, and prognosis of human RCC.…”

ROS Overproduction Sensitises Myeloma Cells to Bortezomib-Induced Apoptosis and Alleviates Tumour Microenvironment-Mediated Cell Resistance

“…Mitophagy is an autophagic process of mitochondria capture and degradation by lysosomes. Moreover, the process of autophagy seems a general response to AUR or more generally to TXNRD1 inhibition in solid cancers [37][38][39]. MM cells synthesize large amounts of immunoglobulins and autophagy is a process by which MM cells protect themselves from unfolded or misfolded proteins.…”

Opuntiaspp.: Characterization and Benefits in Chronic Diseases

“…Likewise, glycoprotein isolated from O. ficus-indica var. saboten MAKINO (an Opuntia variety used in folk medicine in Korea) exerts potent antioxidant and hypolipidemic properties evidenced by a protective effect on mice treated with triton WR-1339, an inhibitor of lipoprotein lipase [66]. It is to note that the ingestion of Opuntia prickly pears also improves the platelet function and haemostatic balance, thus contributing to prevent the atherosclerotic risk [63].…”