CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial–mesenchymal transition, G2/M phase transition, and PANoptosis

Abstract

Background Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate. Methods By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism. Results Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way. Conclusions CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC.

PANoptosis: A Cell Death Characterized by Pyroptosis, Apoptosis, and Necroptosis

“…71 In addition, the activation of pyroptosis, apoptosis and necroptosis (PANoptosis) promotes cancer cell death, thus preventing adrenocortical carcinoma and melanoma development. 72,73 In addition to tumors, PANoptosis also occurs in the process of acute respiratory distress syndrome (ARDS) and acute lung injury, which is manifested by the formation of ASC-caspase-8-RIP3 complex accompanied by caspase-3, GSDMD, phosphorylated MLKL, ZBP1 increased. 74,75 A study showed that genes associated with PANoptosis were differentially expressed in mice middle cerebral artery ischemia-reperfusion injury and control brain tissue samples.…”

“… 71 In addition, the activation of pyroptosis, apoptosis and necroptosis (PANoptosis) promotes cancer cell death, thus preventing adrenocortical carcinoma and melanoma development. 72 , 73 …”

ESCO2's Oncogenic Role in Human Tumors: A Pan-Cancer Analysis and Experimental Validation

“…6D). Cell cycle kinase family member Cyclin-dependent kinase 1 (CDK1) signi cantly impacts cell cycle progression [16,17] . CDK1 overexpression has been found in many cancers, including gastric cancer, ovarian cancer, oral squamous cell carcinoma, liver cancer, and breast cancer [18] .…”

Identification of Key Genes and Related Drugs of Adrenocortical Carcinoma by Integrated Bioinformatics Analysis

“…Cyclin-dependent kinase 1 (CDK1) belongs to a family of cell cycle kinases that are involved in the transition of the cell cycle from the G2 to M phase of mitosis, and upon abnormal regulation, uncontrolled cell proliferation would occur, which would eventually cause tumorigenesis [33]. In ACC, high expression of CDK1 accelerates the epithelial-mesenchymal transition (EMT) while promoting cell proliferation, in addition to altering the cell cycle by regulating the interactions of UBE2C and AURKA/B [34]. An in vitro experiment exploring the interaction between CDK1 and centromeric protein (CENPF) revealed that the G2/M phase transition and cell proliferation were activated during mitosis in the ACC cell line SW13 under the effects of CDK1 and CENPF, which could essentially explain the poor prognosis of ACC [35].…”