In-Chul Park

We have previously defined the constitutive photomorphogenic protein 1 (COP1) gene as a therapeutic target in hepatocellular carcinoma (HCC). A recent study demonstrated that COP1 induces non‐alcoholic fatty liver disease (NAFLD), a precursor to HCC, in normal hepatocytes and that reducing COP1 expression significantly improves high‐fat diet‐induced hepatic steatosis. Thus, in this study, we investigated if the function of COP1 was associated with HCC metabolism and evolution. Silencing of COP1 expression by a target siRNA significantly suppressed long‐term colony formation in Huh7, HepG2, Huh1, and PLC/PRF/5 HCC cell lines. RNA sequencing of COP1‐silenced Huh7 and HepG2 cells revealed the same directional regulation of 24 (14 up‐ and 10 down‐regulated) genes. Notable molecular alterations were upregulation of AKR1D1 and downregulation of TMEM65, which involves negative regulation of lipid metabolism and promotion of metastasis, respectively. Correlation analysis using GEPIA2 supported inverse relationship between COP1 and AKR1D1 expression and positive relationship between COP1 and TMEM65 expression in HCC clinical samples. Targeting of COP1 reduced fat accumulation and metastatic potential in both HCC parental cells and CD133 ⁺ liver cancer stem cells. Overexpression of COP1 reversed the phenotypic changes. Collectively, our findings indicate that the COP1 is functionally correlated with HCC lipid metabolism and stemness.

Kim DG, et al. J Breast Cancer. 2026 ;29:e19. https://doi.org/10.4048/jbc.2026.0016

Ferroptosis is an iron-dependent regulated cell death characterized by lipid peroxidation accumulation. Due to the high iron demand of cancer cells, targeting ferroptosis is considered a promising approach for cancer therapy. This study aimed to elucidate the mechanisms underlying the differences in ferroptosis sensitivity in non-small cell lung cancer (NSCLC) cells and identify strategies to overcome ferroptosis resistance. H1299 cells were more sensitive to cysteine deprivation-induced ferroptosis and exhibited higher transferrin receptor (TfR) expression than H460 cells. Transferrin enhanced ferroptosis in cysteine-deprived H1299 cells, while TfR knockdown reduced ferroptosis, suggesting the involvement of TfR/transferrin system in this process. In H460 cells with low TfR expression, transferrin treatment did not induce ferroptosis under cysteine deprivation, indicating that the TfR/transferrin system was not involved. However, treatment with cell-permeable ferric ammonium citrate increased the sensitivity of ferroptosis to cysteine deprivation or RSL3 treatment. In conclusion, iron overload could be a potential strategy to overcome ferroptosis resistance in NSCLC.

Paclitaxel resistance and recurrence are major obstacles in ovarian cancer, which is the leading cause of death among gynecologic cancers. During cancer cell progression, cyclin-dependent kinase 1 (CDK1) drives cells through the G2 phase and into mitosis. In this study, we demonstrated that CDK1 played a crucial role in switching paclitaxel-resistant ovarian cancer cells from mitotic arrest to apoptosis following combined treatment with paclitaxel and duloxetine, an antidepressant known as a serotonin-norepinephrine reuptake inhibitor (SNRI). Cell viability was assessed by MTT assay. Apoptotic cell death and mitochondrial membrane potential (MMP) were detected by flow cytometry. Protein expression levels were explored using western blotting. Mitochondrial and cytosolic fractionation were performed to determine the mitochondrial localization of proteins. Immunofluorescence was used to detect protein expression levels and localization. Combined treatment with paclitaxel and duloxetine induced apoptotic cell death in paclitaxel-resistant ovarian cancer cells. We suggested that combined treatment of these drugs induced CDK1 activation and increased mitochondrial localization of activated CDK1, which caused phosphorylation of the antiapoptotic Bcl-2 and Bcl-xL proteins. Selective CDK1 inhibitors blocked Bcl-2 and Bcl-xL phosphorylation induced by paclitaxel and duloxetine, and strongly suppressed apoptotic cell death. Furthermore, we demonstrated that S6K is a potential upstream mediator of the proapoptotic activation of CDK1. Taken together, switching CDK1 to a proapoptotic role through the combination of paclitaxel and duloxetine could overcome paclitaxel resistance in ovarian cancer cells, providing promising therapeutic strategies for treating paclitaxel-resistant ovarian cancer.

Ferroptosis, a regulated form of cell death dependent on reactive oxygen species (ROS), is characterized by iron accumulation and lethal lipid peroxidation. Mitochondria serve as the primary source of ROS and thus play a crucial role in ferroptosis initiation and execution. This study highlights the role of mitochondrial ROS and the significance of voltage-dependent anion channel 1 (VDAC1) oligomerization in ferroptosis induced by cysteine deprivation or ferroptosis-inducer RSL3. Our results demonstrate that the mitochondria-targeted antioxidants MitoQ and MitoT effectively block ferroptosis induction and that dysfunction of complex III of the mitochondrial electron transport chain contributes to ferroptosis induction. Pharmacological inhibitors that target VDAC1 oligomerization have emerged as potent suppressors of ferroptosis that reduce mitochondrial ROS production. These findings underscore the critical involvement of mitochondrial ROS production via complex III of the electron transport chain and the essential role of VDAC1 oligomerization in ferroptosis induced by cysteine deprivation or RSL3. This study deepens our understanding of the intricate molecular networks governing ferroptosis and provides insights into the development of novel therapeutic strategies targeting dysregulated cell death pathways.

Tribbles pseudokinase 3 (TRIB3), a member of the mammalian Tribbles family, is implicated in multiple biological processes. This study aimed to investigate the biological functions of TRIB3 in lung cancer and its effect on amino acid-deprived lung cancer cells. TRIB3 mRNA expression was elevated in lung cancer tissues and cell lines compared to normal lung tissues and cells. TRIB3 knockdown markedly reduced the viability and proliferation of H1299 lung cancer cells. Deprivation of amino acids, particularly arginine, glutamine, lysine, or methionine, strongly increased TRIB3 expression via ATF4 activation in H1299 lung cancer cells. Knockdown of TRIB3 led to transcriptional downregulation of ATF4 and reduced AKT activation induced by amino acid deprivation, ultimately increasing the sensitivity of H1299 lung cancer cells to amino acid deprivation. Additionally, TRIB3 knockdown enhanced the sensitivity of H1299 cells to V-9302, a competitive antagonist of transmembrane glutamine flux. These results suggest that TRIB3 is a pro-survival regulator of cell viability in amino acid-deficient tumor microenvironments and a promising therapeutic target for lung cancer treatment.

Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have been effective targeted therapies for non-small cell lung cancer (NSCLC), most advanced NSCLC inevitably develop resistance to these therapies. Combination therapies emerge as valuable approach to preventing, delaying, or overcoming disease progression. Duloxetine, an antidepressant known as a serotonin-noradrenaline reuptake inhibitor, is commonly prescribed for the treatment of chemotherapy-induced peripheral neuropathy. In the present study, we investigated the combined effects of duloxetine and EGFR-TKIs and their possible mechanism in NSCLC cells. Compared with either monotherapy, the combination of duloxetine and EGFR-TKIs leads to synergistic cell death. Mechanistically, duloxetine suppresses 70-kDa ribosomal protein S6 kinase 1 (p70S6K1) activity through mechanistic target of rapamycin complex 1 (mTORC1), and this effect is associated with the synergistic induction of cell death of duloxetine combined with EGFR-TKIs. More importantly, activating transcription factor 4 (ATF4)-induced regulated in development and DNA damage response 1 (REDD1) is responsible for the suppression of mTORC1/S6K1 activation. Additionally, we found that the combination effect was significantly attenuated in REDD1 knockout NSCLC cells. Taken together, our findings reveal that the ATF4/REDD1/mTORC1/S6K1 signaling axis, as a novel mechanism, is responsible for the synergistic therapeutic effect of duloxetine with EGFR-TKIs. These results suggest that combining EGFR-TKIs with duloxetine appears to be a promising way to improve EGFR-TKI efficacy against NSCLC.

Thioredoxin-interacting protein (TXNIP) is sensitive to oxidative stress and is involved in the pathogenesis of various metabolic, cardiovascular, and neurodegenerative disorders. Therefore, several studies have suggested that TXNIP is a promising therapeutic target for several diseases, particularly cancer and diabetes. However, the regulation of TXNIP expression under amino acid (AA)-restricted conditions is not well understood. In the present study, we demonstrated that TXNIP expression was promoted by the deprivation of AAs, especially arginine, glutamine, lysine, and methionine, in non-small cell lung cancer (NSCLC) cells. Interestingly, we determined that increased TXNIP expression induced by AA deprivation was associated with nuclear factor erythroid 2-related factor 2 (NRF2) downregulation, but not with activating transcription factor 4 (ATF4) activation. Furthermore, N-acetyl-l-cysteine (NAC), a scavenger of reactive oxygen species (ROS), suppressed TXNIP expression in NSCLC cells deprived of AA. Collectively, the induction of TXNIP expression by AA deprivation was mediated by ROS production, potentially through NRF2 downregulation. Our findings suggest that TXNIP expression may be associated with the redox homeostasis of AA metabolism and provide a possible rationale for a therapeutic strategy to treat cancer with AA restriction.