Retraction Note: PI3K/Akt pathway and Nanog maintain cancer stem cells in sarcomas
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Targeting AKT as a promising strategy for SOX2-positive, chemoresistant osteosarcoma
Osteosarcoma (OS) is the most prevalent type of primary malignant bone cancer and currently lacks effective targeted treatments. Increasing evidence indicates that SOX2 overexpression is a primary driver of OS. By screening a small-molecule kinase inhibitor library, we identified AKT as a kinase essential for robust SOX2 expression in OS cells. AKT was found to be frequently overexpressed in OS and positively correlated with SOX2 protein levels. We demonstrated that AKT has no effect on SOX2 transcription but promotes SOX2 protein stability. Mechanistically, AKT binds to and phosphorylates SOX2 at T116, preventing SOX2 ubiquitination and proteasome-dependent degradation by ubiquitin E3 ligases UBR5 and STUB1. Moreover, we found that AKT-SOX2 axis is a significant modulator of cancer stemness and chemoresistance and that the combination of AKT inhibitor MK2206 and cisplatin resulted in a synergistic and potent inhibition of OS tumor growth in the PDX model. In conclusion, we identified a critical role for AKT in promoting SOX2 overexpression, tumor stemness, and chemoresistance in OS, and provided evidence that targeting AKT combined with chemotherapy may hold promise for treating refractory OS.
Combined Inhibition of PI3K and STAT3 signaling effectively inhibits bladder cancer growth
Bladder cancer is characterized by aberrant activation of the phosphatidylinositol-3-OH kinase (PI3K) signaling, underscoring the significance of directing therapeutic efforts toward the PI3K pathway as a promising strategy. In this study, we discovered that PI3K serves as a potent therapeutic target for bladder cancer through a high-throughput screening of inhibitory molecules. The PI3K inhibitor demonstrated a robust anti-tumor efficacy, validated both in vitro and in vivo settings. Nevertheless, the feedback activation of JAK1-STAT3 signaling reinstated cell and organoid survival, leading to resistance against the PI3K inhibitor. Mechanistically, the PI3K inhibitor suppresses PTPN11 expression, a negative regulator of the JAK-STAT pathway, thereby activating STAT3. Conversely, restoration of PTPN11 enhances the sensitivity of cancer cells to the PI3K inhibitor. Simultaneous inhibition of both PI3K and STAT3 with small-molecule inhibitors resulted in sustained tumor regression in patient-derived bladder cancer xenografts. These findings advocate for a combinational therapeutic approach targeting both PI3K and STAT3 pathways to achieve enduring cancer eradication in vitro and in vivo, underscoring their promising therapeutic efficacy for treating bladder cancer.
FBXO22 promotes HCC angiogenesis and metastasis via RPS5/AKT/HIF-1α/VEGF-A signaling axis
The gene F-box only protein 22 (FBXO22) has been discovered to promote the development of liver cancer tumors. Nevertheless, there remains considerable ambiguity regarding the involvement of FBXO22 in the processes of angiogenesis and metastasis in hepatocellular carcinoma (HCC). Our study has confirmed a significant upregulation of FBXO22 expression in both HCC samples and cellular models. The increased level of FBXO22 correlates strongly with the number of tumors, presence of vascular invasion, and poor prognosis. Experimental investigations have shown that FBXO22 significantly enhances angiogenesis and metastasis of HCC both in vitro and in vivo. Mechanistically, FBXO22 interacts with and ubiquitinates 40S ribosomal protein S5 (RPS5) on Lys85, thereby promoting its K48-linked ubiquitin-mediated degradation in the cytoplasm. Following a decrease in the expression of RPS5, activation of downstream PI3K/AKT signaling pathway occurs, leading to elevated levels of HIF-1α and vascular endothelial growth factor A (VEGF-A). Our study has shown that FBXO22 facilitates HCC angiogenesis and metastasis via the RPS5/AKT/HIF-1α/VEGF-A signaling axis. Notably, inhibition of FBXO22 enhances the efficacy of Lenvatinib both in vitro and in vivo. Therefore, FBXO22 may present itself as a potential target for therapeutic intervention in the treatment of HCC.
Anaerobic metabolism promotes breast cancer survival via Histone-3 Lysine-18 lactylation mediating PPARD axis
Histone lactylation plays a crucial role in cancer progression, but its impact on breast cancer (BC) tumorigenesis is still unclear. We utilized chromatin immunoprecipitation sequencing with H3K18la antibodies, transcriptomics of clinical BC samples, and proteomics and ATAC-seq analyses of in vivo tumors to identify the genes regulated by H3K18la and the transcription factor PPARD. qPCR and Western blot assays were used to detect expressions of molecules. We discovered that H3K18la levels were higher in BC tissues compared to adjacent non-cancerous tissues. H3K18la promoted the expression of PPARD, which in turn influenced the transcription of AKT, but not ILK. ATAC-seq analysis revealed that glycolysis in BC cells enhanced chromatin accessibility. Additionally, we confirmed that HDAC2 and HDAC3 act as “erasers” for H3 lysine lactylation. During the proteomics analysis, AKT-phosphorylation in the aerobic respiration inhibitor group exhibited an apparent disparity and activity. Our study demonstrated that changes in H3K18la in BC and its downstream transcription factor PPARD support cell survival under anaerobic glycolysis conditions. PPARD accelerated cancer proliferation by promoting the transcription and phosphorylation of AKT. This highlights the therapeutic potential of targeting the H3K18la/PPARD/AKT axis in breast cancer, providing new insights into epigenetic regulation and cancer metabolism (Trial registration: The study was approved by the Research Ethics Committee Shandong Provincial Third Hospital (KYLL-2023057; https://www.medicalresearch.org.cn/)).
TFCP2L1 drives stemness and enhances their resistance to Sorafenib treatment by modulating the NANOG/STAT3 pathway in hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is a prevalent and aggressive malignancy associated with high risks of recurrence and metastasis. Liver cancer stem cells (CSCs) are increasingly recognized as pivotal drivers of these processes. In our previous research, we demonstrated the involvement of TFCP2L1 in maintaining the pluripotency of embryonic stem cells. However, its relevance to liver CSCs remains unexplored. In this study, we report an inverse correlation between TFCP2L1 protein levels in HCC tissue and patient outcomes. The knockdown of TFCP2L1 significantly reduced HCC cell proliferation, invasion, metastasis, clonal formation, and sphere-forming capacity, while its overexpression enhanced these functions. In addition, experiments using a nude mouse model confirmed TFCP2L1’s essential role in liver CSCs’ function and tumorigenic potential. Mechanistically, we showed that TFCP2L1 promotes the stemness of CSCs by upregulating NANOG, which subsequently activates the JAK/STAT3 pathway, thereby contributing to HCC pathogenesis. Importantly, we identified a specific small molecule targeting TFCP2L1’s active domain, which, in combination with Sorafenib, sensitizes hepatoma cells to treatment. Together, these findings underscore TFCP2L1’s pathological significance in HCC progression, supporting its potential as a prognostic biomarker and therapeutic target in this disease.
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