Targeting Bmi1 for Enhancing Anoikis Sensitivity and Inhibiting Metastasis in Colorectal Cancer.

BACKGROUND/AIM: Patients diagnosed with advanced metastatic colorectal cancer (CRC) confront a bleak prognosis characterized by low survival rates. Anoikis, the programmed apoptosis resistance exhibited by metastatic cancer cells, is a crucial factor in this scenario. MATERIALS AND METHODS: We employed bulk flow cytometry and RT-qPCR assays, conducted in vivo experiments with mice and zebrafish, and analyzed patient tissues to examine the effects of the B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi1)-midkine (MDK) axis on the cellular response to anoikis. Bmi1 is pivotal in tumorigenesis. This study elucidated the involvement of Bmi1 in conferring anoikis resistance in CRC and explored its downstream targets associated with metastasis. RESULTS: Elevated levels of Bmi1 expression correlated with distant metastasis in CRC. Suppression of Bmi1 significantly diminished the metastatic potential of CRC cells. Inhibition of Bmi1 led to an increase in the proportion of apoptotic SW620 cells detached from the matrix. This effect was further enhanced by the addition of irinotecan, a topoisomerase I inhibitor. Furthermore, Bmi1 was found to synergize with MDK in modulating CRC viability, with consistent expression patterns observed in in vivo models and clinical tissue specimens. In summary, Bmi1 acted as a regulator of CRC metastatic capability by conferring anoikis resistance. Additionally, it collaborated with MDK to facilitate invasion and distant metastasis. CONCLUSION: Targeting Bmi1 may offer a promising adjunctive therapeutic strategy when administering traditional chemotherapy regimens to patients with advanced CRC.

Targeting the CDK7-MDK axis to suppresses irinotecan resistance in colorectal cancer.

AIMS: Colorectal cancer (CRC) remains a major global health issue, with metastatic cases presenting poor prognosis despite advances in chemotherapy and targeted therapy. Irinotecan, a key drug for advanced CRC treatment, faces challenges owing to the development of resistance. This study aimed to understand the mechanisms underlying irinotecan resistance in colorectal cancer. MAIN METHODS: We created a cell line resistant to irinotecan using HT29 cells. These resistant cells were utilized to investigate the role of the CDK7-MDK axis. We employed bulk RNA sequencing, conducted in vivo experiments with mice, and analyzed patient tissues to examine the effects of the CDK7-MDK axis on the cellular response to irinotecan. KEY FINDINGS: Our findings revealed that HT29 cells resistant to irinotecan, a crucial colorectal cancer medication, exhibited significant phenotypic and molecular alterations compared to their parental counterparts, including elevated stem cell characteristics and increased levels of cytokines and drug resistance proteins. Notably, CDK7 expression was substantially higher in these resistant cells, and targeting CDK7 effectively decreased their survival and tumor growth, enhancing irinotecan sensitivity. RNA-seq analysis indicated that suppression of CDK7 in irinotecan-resistant HT29 cells significantly reduced Midkine (MDK) expression. Decreased CDK7 and MDK levels, achieved through siRNA and the CDK7 inhibitor THZ1, enhanced the sensitivity of resistant HT29 cells to irinotecan. SIGNIFICANCE: Our study sheds light on how CDK7 and MDK influence irinotecan resistance in colorectal and highlights the potential of MDK-targeted therapies. We hypothesized that irinotecan sensitivity and overall treatment efficacy would improve by inhibiting MDK. This finding encourages a careful yet proactive investigation of MDK as a therapeutic target to enhance outcomes in colorectal cancer patients.

Skp2-mediated Zeb1 expression facilitates cancer migration by a ubiquitination-independent pathway.

AIMS: Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most dismal malignancies worldwide. Despite multidisciplinary involvement in interventions involving surgery, radiotherapy, and chemotherapy, most pancreatic cancer patients eventually develop distant metastasis. S-phase kinase-associated protein 2 (Skp2) plays an important role in cell-cycle regulation in pancreatic cancer. However, the role of Skp2 in individualized PDAC treatment is largely unknown. MAIN METHODS: Immunoblotting, quantitative reverse transcription polymerase chain reaction, cell viability test, chromatin immunoprecipitation assay, and xenograft in vivo assay were performed in parental and Skp2-depleted cells. The immunohistochemistry of Skp2 was analyzed on the tissue microarrays of 45 PDAC cases and mice tissues. KEY FINDINGS: In this study, we observed that Skp2 is a marker for poor prognosis in PDAC patients. Upregulation of the inhibitor of κB (IκB)-inducing kinase-nuclear factor kappa B (NF-κB) signal cascade mediated Skp2 expression thereby promoting epithelial-mesenchymal transition (EMT). Depletion of NF-κB-associated signaling effectively prevented Skp2-mediated pancreatic cancer cell migration. As a functional consequence, Skp2 orchestrated with Myc to induce zinc finger E-box binding homeobox 1 (Zeb1) transcription by recruiting p300 to the Zeb1 promoter independent of Skp2 E3-ligase activity. Therefore, blockade of Skp2 could significantly reduce the expression of Zeb1 and inhibit cancer cell migration. In conclusion, Skp2 regulated Zeb1 activity to control the migration and invasion abilities of pancreatic cancer cells. Skp2 expression in PDAC may affect cell vulnerability to standard chemotherapy regimens. SIGNIFICANCE: Therefore, in patients with PDAC, modulation of Skp2 expression could be a novel strategy for preventing cancer cell metastasis.