Platinum-induced upregulation of ITGA6 promotes chemoresistance and spreading in ovarian cancer
Ontology highlight
ABSTRACT:
SUBMITTER: Dr. Alice Gambelli
PROVIDER: S-SCDT-10_1038-S44321-024-00069-3 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Ovarian cancer (OC), the second most common form of gynecologic malignancy, has a poor prognosis and is often discovered in the late stages. Platinum-based chemotherapy is the first line of therapy. Nevertheless, treatment OC has proven challenging due to toxicity and the development of acquired resistance to therapy. Tumor microenvironment (TME) has been associated with platinum chemoresistance. Malignant ascites has been used as OC tumor microenvironment and its ability to induce platinum chemoresistance has been investigated. Our results suggest that exposure to OC ascites induces platinum chemoresistance in 11 of 13 cases (85 %) on OC cells. In contrast, 75 % of cirrhotic ascites (3 of 4) failed to confer platinum chemoresistance to OC cells. Cytokine array analysis revealed that IL -6 and to a lesser extent HGF were enriched in OC ascites, whereas IL -22 was enriched in cirrhotic ascites. Pharmaceutical inhibitors targeting the IL -6/ JAK pathway were mildly effective in overcoming platinum chemoresistance induced by malignant ascites. In contrast, crizotinib, an HGF/c- MET inhibitor, and 2-hydroxyestradiol (2HE2) were effective in restoring platinum chemosensitivity to OC. Our results demonstrate the importance of OC ascites in supporting platinum chemoresistance and the potential of combination therapy to restore chemosensitivity of OC cells.
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Project description:Ovarian cancer is the fifth most deadly cancer in women in the United States and despite advances in surgical and chemotherapeutic treatments survival rates have not significantly improved in decades. The poor prognosis for ovarian cancer patients is largely due to the extremely high (80%) recurrence rate of ovarian cancer and because the recurrent tumors are often resistant to the widely utilized platinum-based chemotherapeutic drugs. In this study, expression of Rad6, an E2 ubiquitin-conjugating enzyme, was found to strongly correlate with ovarian cancer progression. Furthermore, in ovarian cancer cells Rad6 was found to stabilize ?-catenin promoting stem cell-related characteristics, including expression of stem cell markers and anchorage-independent growth. Cancer stem cells can promote chemoresistance, tumor recurrence and metastasis, all of which are limiting factors in treating ovarian cancer. Thus it is significant that Rad6 overexpression led to increased resistance to the chemotherapeutic drug carboplatin and correlated with tumor cell invasion. These findings show the importance of Rad6 in ovarian cancer and emphasize the need for further studies of Rad6 as a potential target for the treatment of ovarian cancer.
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Project description:BackgroundColorectal cancer (CRC), a prevalent gastrointestinal malignant disease, causes substantial morbidity and mortality. Identification of novel prognostic biomarkers and therapeutic targets is critically needed to improve patient outcomes. Although solute carrier family 12 member 8 (SLC12A8) has high expression in various tumors and affects tumor progression, its role in CRC remains unclear. The aim of this study was to investigate the functions of SLC12A8 in CRC.MethodsSLC12A8 expression and its association with clinical significance in CRC patients were explored via multiple public databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), The Human Protein Atlas (HPA), The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN), and Kaplan-Meier plotter. The effects of SLC12A8 on the CRC cell apoptosis, epithelial-mesenchymal transition (EMT), reactive oxygen species (ROS) production, and sensitivity to oxaliplatin were verified by in vitro experiments.ResultsSLC12A8 expression was upregulated in CRC tissues compared with normal colorectal tissues. Furthermore, high expression of SLC12A8 was associated with poorer prognosis in CRC patients. Pathway enrichment analyses revealed SLC12A8 involvement in oxidative stress and transforming growth factor-beta (TGF-β) signaling. Experiments in CRC cells showed that SLC12A8 upregulation promoted apoptosis resistance, EMT, and inhibited ROS production. Moreover, SLC12A8 knockdown enhanced the sensitivity of CRC cells to oxaliplatin chemotherapy.ConclusionsOur integrative analyses identify SLC12A8 as a candidate biomarker for CRC progression. Targeting SLC12A8 may improve patient responses to oxaliplatin-based treatment regimens.
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Project description:ATP7B is a hepato-specific Golgi-located ATPase, which plays a key role in the regulation of copper (Cu) homeostasis and signaling. In response to elevated Cu levels, ATP7B traffics from the Golgi to endo-lysosomal structures, where it sequesters excess copper and further promotes its excretion to the bile at the apical surface of hepatocytes. In addition to liver, high ATP7B expression has been reported in tumors with elevated resistance to platinum (Pt)-based chemotherapy. Chemoresistance to Pt drugs represents the current major obstacle for the treatment of large cohorts of cancer patients. Although the mechanisms underlying Pt-tolerance are still ambiguous, accumulating evidence suggests that lysosomal sequestration of Pt drugs by ion transporters (including ATP7B) might significantly contribute to drug resistance development. In this context, signaling mechanisms regulating the expression of transporters such as ATP7B are of great importance. Considering this notion, we investigated whether ATP7B expression in Pt-resistant cells might be driven by transcription factor EB (TFEB), a master regulator of lysosomal gene transcription. Using resistant ovarian cancer IGROV-CP20 cells, we found that TFEB directly binds to the predicted coordinated lysosomal expression and regulation (CLEAR) sites in the proximal promoter and first intron region of ATP7B upon Pt exposure. This binding accelerates transcription of luciferase reporters containing ATP7B CLEAR regions, while suppression of TFEB inhibits ATP7B expression and stimulates cisplatin toxicity in resistant cells. Thus, these data have uncovered a Pt-dependent transcriptional mechanism that contributes to cancer chemoresistance and might be further explored for therapeutic purposes.
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Project description:BACKGROUND:Ovarian cancer is the most lethal gynecologic cancer. Chemoresistance, especially platinum-resistance, is closely related to metastasis of ovarian cancer, however, the molecular basis by which links chemoresistance and metastasis remains vague. Disordered arachidonic acid (AA) metabolism has been shown to play an important role in the advanced ovarian cancer. This study aimed to explore the underlying mechanism involving eicosanoid metabolism that controlling chemoresistance and metastasis of ovarian cancer. METHODS:Cisplatin (DDP)-resistant SKOV3 (SKOV3-R) cells were constantly induced. Ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was performed to determine the AA metabolism in SKOV3 and SKOV3-R cells. Half maximal inhibitory concentration (IC50) and percentage of cell viability were tested using cell counting kit 8 (CCK-8). Realtime quantitative PCR (qPCR) and immunohistochemistry (IHC) were used to evaluate indicated genes and proteins respectively. Bioinformatic analysis and chromatin immunoprecipitation (ChIP) were performed to predict and identify the co-transcription factor of interest genes. Tumor growth and metastasis in the liver were assessed with nude mice by subcutaneously injection of SKOV3-R cells. RESULTS:SKOV3-R cells expressed higher multidrug resistance-associated proteins (MRPs) MRP1 and MRP4. They showed enhanced metastatic ability and produced increased AA-derived eicosanoids. Mechanistically, MRPs, epithelial mesenchymal transition (EMT) markers Snail and Slug, as well as key enzymes involved in AA-metabolism including 12-lipoxygenase (12LOX) were transcribed by the mutual transcription factor SP1 which was consistently upregulated in SKOV3-R cells. Inhibition of SP1 or 12LOX sensitized SKOV3-R cells to DDP and impaired metastasis in vitro and in vivo. CONCLUSION:Our results reveal that SP1-12LOX axis signaling plays a key role in DDP-resistance and metastasis, which provide a new therapeutic target for ovarian cancer.
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