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The glutaminase inhibitor BPTES reverses activation of mTOR signaling in LAPTM5-knockdown ER + BC cells. (A) Protein expression of key molecules of glutamine metabolism and mTOR signaling in the blank and LAPTM5-sh3 (knockdown) MCF-7 and T47D cells when treated with docetaxel or the SLC1A5 inhibitor BPTES. (B-K) The relative protein expression of Raptor, p-S6K1, and p-4EBP1 in MCF-7 and T47D cells. (L) Protein expression of key molecules of glutamine metabolism and mTOR signaling in the blank and LAPTM5-OE (overexpessing) MCF-7 and T47D cells when treated with docetaxel. The relative protein expression of Raptor, p-S6K1, and p-4EBP1 in MCF-7 (M) and T47D (N) cells. * P<0.05, ** P<0.01, and *** P<0.001, compared with the blank MCF-7 and T47D cells. LAPTM5, lysosomal protein transmembrane 5; ER + BC, estrogen receptor-positive breast cancer; S6K1, ribosomal protein S6 kinase 1; 4EBP1, eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1; p-, phosphorylated.
Source publication
Estrogen receptor‑positive (ER+) breast cancer (BC) is a malignancy that is prone to metastasis to the spine, which is difficult to treat and often results in poor prognosis. However, the mechanism underlying the tumorigenesis and spinal metastasis of ER+ BC remains unclear. Lysosomal protein transmembrane 5 (LAPTM5) has been reported as a tumor su...
Contexts in source publication
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... our speculation. As shown in Fig. 3E-G, the glutamine transporters SLC1A5 and GLS1 showed significant upregulated expression when LAPTM5 was inhibited, illustrating the effect of LAPTM5 on glutamine metabolism. In addition, no significant changes were found in the glutaminase 2 (GLS2) expression between LAPTM5-silenced and control ER + BC cells (Fig. S4). In addition as shown in Fig. 3E-G, the mTOR complex 1 (mTORC1) component Raptor and its downstream factors ribosomal protein S6 kinase B1 (S6K1) and eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) were found to be significantly activated in the LAPTM5-sh3 cells. After phosphorylation of S6K1 (p-S6K1) and 4EBP1 ...
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... inhibitor BPTES blocks the effect of LAPTM5 inhibition. To further elucidate the molecular mechanism of LAPTM5 in regulating ER + BC, we treated blank or LAPTM5-sh3 cells with docetaxel, the glutaminase inhibitor BPTES, or both docetaxel and BPTES. As shown in Fig. 4A, after treatment with docetaxel alone, the activation of mTORC1 and the phosphorylation of its downstream factors S6K1 and 4EBP1 was suppressed in the blank ER + BC cells by the chemotherapeutic drug. However, in LAPTM5-sh3 cells, Raptor, p-S6K1 and p-4EBP1 were even more highly activated than in cells without docetaxel treatment, ...
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... ER + BC cells by the chemotherapeutic drug. However, in LAPTM5-sh3 cells, Raptor, p-S6K1 and p-4EBP1 were even more highly activated than in cells without docetaxel treatment, indicating that downregulation of LAPTM5 expression decreased the chemosensitivity of ER + BC cells. In contrast, the opposite results were observed in the LAPTM5-OE cells (Fig. 4L). Fig. 4B-K, M and N shows the quantitative analysis of the protein levels of Raptor, p-S6K1, and p-4EBP1 in the MCF-7 and T47D cell lines. In addition, BPTES treatment inhibited the activation of mTORC1 signaling in both blank and LAPTM5-sh3 cells with or without docetaxel treatment, demonstrating that glutamine-dependent mTORC1 ...
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... by the chemotherapeutic drug. However, in LAPTM5-sh3 cells, Raptor, p-S6K1 and p-4EBP1 were even more highly activated than in cells without docetaxel treatment, indicating that downregulation of LAPTM5 expression decreased the chemosensitivity of ER + BC cells. In contrast, the opposite results were observed in the LAPTM5-OE cells (Fig. 4L). Fig. 4B-K, M and N shows the quantitative analysis of the protein levels of Raptor, p-S6K1, and p-4EBP1 in the MCF-7 and T47D cell lines. In addition, BPTES treatment inhibited the activation of mTORC1 signaling in both blank and LAPTM5-sh3 cells with or without docetaxel treatment, demonstrating that glutamine-dependent mTORC1 signaling ...
Citations
... We also found a combination of bone metastases in all patients, with spinal metastases being the most common (78.78%) (Yang et al., 2022a). This may be due to higher levels of the chemokine CXC3L1/CXC3R1 in the spine than in other bones, which can promote adhesion and migration of breast cancer cells (Meng et al., 2022). ...
The rich blood supply of the bone marrow provides favorable conditions for tumor cell proliferation and growth. In the disease’s early stages, circulating tumor cells can escape to the bone marrow and form imperceptible micro metastases. These tumor cells may be reactivated to regain the ability to grow aggressively and eventually develop into visible metastases. Symptomatic bone marrow metastases with abnormal hematopoiesis solid tumor metastases are rare and have poor prognoses. Treatment options are carefully chosen because of the suppression of bone marrow function. In this review, we summarized the mechanisms involved in developing bone marrow metastases from tumor cells and the clinical features, treatment options, and prognosis of patients with symptomatic bone marrow metastases from different solid tumors reported in the literature.
... CX3CL1 is originally translated as a transmembrane protein but can be proteolytically processed to produce a soluble chemokine and has been demonstrated to signal via its receptor CX3CR1 [16]. More specifically, a high level of CX3CL1 has been revealed to inhibit the expression of lysosomal protein transmembrane 5, explaining how estrogen receptor-positive breast cancer metastasized to the spine [17]. Furthermore, the expression of CX3CL1 and CX3CR1 in GC tissues was higher than those in adjacent tissues and was promoted in GC tissues from the perineural invasion-positive group compared to the perineural invasion-negative group [18]. ...
C-X3-C motif chemokine ligand 1 (CX3CL1) is a transmembrane protein, and the membranal and soluble forms of CX3CL1 exhibit different functions, although both bind to the CX3CR1 chemokine receptor. The CX3CL1/CX3CR1 axis induces many cellular responses relevant to cancer, such as proliferation, migration, invasion, and apoptosis resistance. Here we attempt to elucidate whether CX3CL1/CX3CR1 is associated with paclitaxel (PTX) resistance in gastric cancer (GC). The Gene Expression Omnibus database was queried to screen for differentially expressed genes in GC cells caused by drug resistance, and CX3CL1 was selected as a candidate. CX3CL1 was overexpressed in PTX-resistant cells and tissues. CX3CL1 loss sensitized GC cells to PTX, promoted apoptosis and DNA damage, and inhibited cell proliferation, migration, and invasion. CX3CR1 reversed the ameliorative effect of CX3CL1 silencing on PTX sensitivity in GC cells. The promotion of PTX resistance by CX3CL1/CX3CR1 was inhibited by impairment of the small GTPase Ras homolog gene family member A (RhoA) pathway in vitro and in vivo. These findings indicate that the CX3CL1/CX3CR1 expedites PTX resistance through the RhoA signaling in GC cells.
... LAPTM5 acts as an oncogene and promotes malignant phenotypes, including metastatic potential, proliferation, and resistance to treatment 11, 12 . Moreover, LAPTM5 also functions as a tumour suppressor in several types of cancer, such as oestrogen receptor-positive breast cancer and neuroblastoma 13,14 . In ccRCC, LAPTM5 functions as an oncogene and promotes cell proliferation, migration, and invasion by activating the RAC1-JNK/p38 axis 15 . ...
Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cell carcinoma with poor prognosis and high mortality. Mutation-mediated inactivation of Von Hippel Lindau (VHL) is a hallmark feature of ccRCC, and it leads to the accumulation of hypoxia-inducible factors (HIFs) and cancer progression. Therefore, further elucidation of the network that regulates the VHL/HIF-1α pathway will provide potential therapeutic targets for the treatment of ccRCC. The results of the current study demonstrated that lysosomal-associated protein transmembrane 5 (LAPTM5) is a novel transcriptional target of HIF-1α and that HIF-1α positively regulates the expression of LAPTM5 in ccRCC cells. Furthermore, the maximum overexpression of LAPTM5 in ccRCC tissues compared with corresponding normal tissues was observed in the pan-cancer analysis. In addition, LAPTM5 overexpression was closely related to metastasis and poor outcomes in ccRCC patients. In addition, LAPTM5 promoted the proliferation, migration and invasion of ccRCC cells. Mechanistically, LAPTM5 regulated the K63-linked ubiquitination of STAT1, enhanced the interaction between STAT1 and JAK2, and induced the phosphorylation of STAT1 at Y701, ultimately promoting the progression of ccRCC. This study reveals a novel HIF-1α/LAPTM5/STAT1 signalling pathway that promotes ccRCC progression and provides potential therapeutic strategies for the treatment of ccRCC.
... The reported articles did not analyze the specific sites of bone metastases. We found that the weight-bearing bone (spine, 26 cases) was the most common site of metastasis, which may be because the level of CXC3L1/CXC3R1 in the spine bone is higher than that in other bones, which can promote the adhesion and migration of breast cancer cells (13). We summarized the literature on breast cancer BMM retrieved from PubMed ( Table 4). ...
Objective
Breast cancer symptomatic bone marrow metastasis (BMM) is rare and has a poor prognosis. Chemotherapy is usually the primary treatment, but it has limited efficacy, resulting in dose reduction and a decrease in quality of life due to the adverse effects of the agent. Other than chemotherapy, there are no other treatment studies for BMM. This study aimed to explore the clinicopathological characteristics of BMM patients with breast cancer, the prognosis using different treatment modalities, and the risk factors that affect the prognosis.
Methods
This retrospective study included patients diagnosed with breast cancer BMM from January 2018 to January 2022 in the Cancer Center of the First Hospital of Jilin University. The analysis focused on the characteristics of the patients, the treatment regimen, and the prognosis.
Results
Of 733 patients with advanced breast cancer, 33 patients were identified with BMM. All patients showed a hemoglobin decrease, and 25 (75.75%) presented with a fever of unknown origin. As for the metastasis breast cancer subtype, 25 (75.75%) were hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) negative, three (9.09%) had HER2 overexpression, and five (15.15%) were triple negative. The BMM patients had a median progression-free survival (PFS) of 7 months (1–21 months) and a median overall survival (OS) of 18 months (2–108 months). Among 25 HR⁺/HER2⁻ BMM patients treated with different modalities, the median OS of the endocrine therapy (ET) group was 23 months, compared with 5 months in the chemotherapy group. Cox proportional hazards models suggested that higher Eastern Cooperative Oncology Group (ECOG) scores and old age were associated with shorter survival.
Conclusion
When breast cancer patients present with anemia and fever of unknown origin, BMM should be considered. For HR⁺/HER2⁻ patients with good physical status and can receive active treatment, CDK4/6 inhibitors combined with ET can be used to control disease progression, improve quality of life, and prolong survival.
Objective:
Testicular germ cell tumors (TGCTs), containing pure seminoma and non-seminoma, occupy the most majority of testicular cancers in adolescents and young men, which has increased dramatically in recent decades. Therefore, it is important to find crucial genes for improving diagnosis and prognosis in TGCTs. However, the diagnostic and prognostic markers of TGCTs are limited.
Methods:
In this study, our main objective is to explore novel potential genes that can be used as diagnostic and prognostic biomarkers in TGCTs. Our study detected 732 differentially expressed genes (DEGs) using three microarray expression profiling datasets from Gene Expression Omnibus (GEO). Multiple analysis was performed to identify the roles of DEGs, including pathway and functional enrichment analysis, protein-protein interaction (PPI) network analysis, module analysis, and survival analysis.
Result:
In total, 322 upregulated genes and 406 downregulated genes were identified as DEGs The functional and pathway enrichment analysis shows that DEGs were highly enriched in multiple biological attributes such as T cell activation, reproduction in multicellular organism, sperm flagellum, antigen processing and presentation Then, seven potential crucial genes were identified via PPI network analysis, module analysis, and survival analysis. Furthermore, 7 potential crucial genes had shown to play a key role in regulating immune cell infiltration level in patients with TGCTs.
Conclusion:
We identified seven potential crucial genes (LAPTM5, NCF2, PECAM1, CD14, COL4A2, ANPEP and RGS1), which may be molecular markers in improving the way of diagnosis and prognosis in TGCTs.
Breast cancer remains the most common malignancy and the leading cause of cancer‑associated mortality in women worldwide. Lysosomal protein transmembrane 5 (LAPTM5), a lysosomal membrane protein, plays an important role in several human malignancies. However, the biological functions and mechanism of LAPTM5 in breast cancer remain unclear. In the present study, the potential tumor‑promoting effect of LAPTM5 was predicted by bioinformatics analysis. LAPTM5 was highly expressed in breast cancer clinical specimens. Moreover, in vitro studies demonstrated that cell proliferation, migration and invasion, as well as the process of epithelial‑mesenchymal transition (EMT) were promoted by LAPTM5 overexpression and were suppressed by LAPTM5 downregulation in vitro. The tumor‑promoting effects of LAPTM5 were also confirmed by xenograft tumor assay in vivo. It was found that the tumor‑promoting effects of LAPTM5 were partly dependent on the activation of the Wnt/β‑catenin signaling pathway. Furthermore, dual‑luciferase and chromatin immunoprecipitation assays verified that the transcription factor forkhead box protein 3 (FOXP3) directly bound to the promoter of LAPTM5 and negatively regulated its expression. Taken together, the present findings indicated that LAPTM5, negatively regulated by FOXP3, promoted the malignant phenotypes of breast cancer through activating the Wnt/β‑catenin signaling pathway.
