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Romanian Journal of Morphology and... 2023Today, many anticancer drugs are used clinically for ovarian cancer, one of the leading causes of cancer-related deaths in women. Phenformin is an antidiabetic drug of...
Today, many anticancer drugs are used clinically for ovarian cancer, one of the leading causes of cancer-related deaths in women. Phenformin is an antidiabetic drug of the biguanide class. It improves the antiproliferative activity in cancer cells. Hypoxia is an important component associated with ovarian cancer and its tumor microenvironment. The aim of this study was to investigate the anticancer effects of Phenformin in SKOV-3 human ovarian cancer cells under hypoxic conditions. SKOV-3 human ovarian cancer cells treated with different doses of Phenformin (0.5 mM, 1 mM, 2 mM, 5 mM) for 24 hours were subjected to WST-1 cell viability assay and Annexin V apoptosis assay. A dose-dependent decrease in cell viability with Phenformin treatment was observed. In addition, Phenformin activated percentage of apoptotic SKOV-3 cancer cells in a dose-dependent manner. In this study, Cobalt(II) chloride (CoCl2) treatment leads to increased hypoxia-inducible factor-1alpha (HIF-1α) expression and Phenformin can recover hypoxic condition. HIF-1α protein expression was significantly correlated with cell viability assay and apoptosis assay. We also found that Phenformin inhibits expression of phosphoinositide-dependent kinase 1 (PDK1) in SKOV-3 ovarian cancer cells. The ability to migrate to cancer cells was significantly reduced in a dose-dependent manner with Phenformin. This data demonstrates that Phenformin treatment can induce apoptosis and inhibit proliferation in ovarian cancer cells under hypoxic conditions. The findings reveal that HIF-1α is a new target for the treatment of ovarian cancer.
Topics: Female; Humans; Antineoplastic Agents; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Ovarian Neoplasms; Phenformin; Tumor Microenvironment
PubMed: 37867353
DOI: 10.47162/RJME.64.3.07 -
Frontiers in Bioscience (Landmark... Aug 2023Activation of the unfolded protein response (UPR) is closely related to the pathogenesis of many metabolic disorders. Accumulating evidence also shows that UPR and...
BACKGROUND
Activation of the unfolded protein response (UPR) is closely related to the pathogenesis of many metabolic disorders. Accumulating evidence also shows that UPR and metabolic signaling pathways are interdependent. The AMP-activated protein kinase (AMPK) signal pathway controls the energy balance of eukaryotes. The aim of this study was therefore to investigate the possible interaction between AMPK signaling and UPR in muscle cells exposed to saturated fatty acids, as well as the potential mechanism.
METHODS
The saturated fatty acid palmitate was used to induce UPR in C2C12 myotubes. Compound C or knockdown of AMPKα with short hairpin RNA (shRNA) were used to inhibit the AMPK signaling pathway in palmitate-treated muscle cells. AMPK signaling in myotubes was activated using 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide (AICAR) or ex229. C2C12 myotubes were pre-treated with taurourdodeoxycholic acid (TUDCA) to inhibit UPR before adding palmitate. Real-time PCR and Western blotting were performed to evaluate the expression of UPR markers and activation of AMPK.
RESULTS
Palmitate treatment induced UPR in C2C12 myotubes while activating AMPK signaling. Inhibition of the AMPK pathway with compound C or AMPK shRNA reduced palmitate-induced activation of UPR, while inhibition of UPR with TUDCA reduced palmitate-induced AMPK activation. This indicates a positive feedback loop between UPR and AMPK. Furthermore, activation of the AMPK pathway with AICAR or ex229 caused a dose-dependent upregulation of UPR markers, including activating transcription factor 4 (ATF4), binding immunoglobulin protein (BIP), and growth arrest and DNA damage-inducible 34 (GADD34) protein.
CONCLUSIONS
These results provide the first evidence that AMPK signaling is involved in the early activation of UPR caused by saturated fatty acids in skeletal muscle. Furthermore, they indicate that physiological or pharmacological activation of the AMPK pathway (e.g., by exercise or phenformin, respectively) can promote muscle health and function, thereby improving the quality of life in individuals with metabolic disorders due to a high-fat diet or obesity.
Topics: Humans; AMP-Activated Protein Kinases; Feedback; Quality of Life; Muscle Cells
PubMed: 37664919
DOI: 10.31083/j.fbl2808159 -
ELife Aug 2023Biguanides, including the world's most prescribed drug for type 2 diabetes, metformin, not only lower blood sugar, but also promote longevity in preclinical models....
Biguanides, including the world's most prescribed drug for type 2 diabetes, metformin, not only lower blood sugar, but also promote longevity in preclinical models. Epidemiologic studies in humans parallel these findings, indicating favorable effects of metformin on longevity and on reducing the incidence and morbidity associated with aging-related diseases. Despite this promise, the full spectrum of molecular effectors responsible for these health benefits remains elusive. Through unbiased screening in , we uncovered a role for genes necessary for ether lipid biosynthesis in the favorable effects of biguanides. We demonstrate that biguanides prompt lifespan extension by stimulating ether lipid biogenesis. Loss of the ether lipid biosynthetic machinery also mitigates lifespan extension attributable to dietary restriction, target of rapamycin (TOR) inhibition, and mitochondrial electron transport chain inhibition. A possible mechanistic explanation for this finding is that ether lipids are required for activation of longevity-promoting, metabolic stress defenses downstream of the conserved transcription factor /Nrf. In alignment with these findings, overexpression of a single, key, ether lipid biosynthetic enzyme, /FAR1, is sufficient to promote lifespan extension. These findings illuminate the ether lipid biosynthetic machinery as a novel therapeutic target to promote healthy aging.
Topics: Humans; Animals; Caenorhabditis elegans; Longevity; Diabetes Mellitus, Type 2; Ethyl Ethers; Ethers; Metformin; Antimalarials; Lipids
PubMed: 37606250
DOI: 10.7554/eLife.82210 -
Cancers Jul 2023Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 10 percent largely due to the intense fibrotic desmoplastic reaction, characterized by...
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 10 percent largely due to the intense fibrotic desmoplastic reaction, characterized by high levels of extracellular matrix (ECM) collagen I that constitutes a niche for a subset of cancer cells, the cancer stem cells (CSCs). Cancer cells undergo a complex metabolic adaptation characterized by changes in metabolic pathways and biosynthetic processes. The use of the 3D organotypic model in this study allowed us to manipulate the ECM constituents and mimic the progression of PDAC from an early tumor to an ever more advanced tumor stage. To understand the role of desmoplasia on the metabolism of PDAC parenchymal (CPC) and CSC populations, we studied their basic metabolic parameters in organotypic cultures of increasing collagen content to mimic in vivo conditions. We further measured the ability of the bioenergetic modulators (BMs), 2-deoxyglucose, dichloroacetate and phenformin, to modify their metabolic dependence and the therapeutic activity of paclitaxel albumin nanoparticles (NAB-PTX). While all the BMs decreased cell viability and increased cell death in all ECM types, a distinct, collagen I-dependent profile was observed in CSCs. As ECM collagen I content increased (e.g., more aggressive conditions), the CSCs switched from glucose to mostly glutamine metabolism. All three BMs synergistically potentiated the cytotoxicity of NAB-PTX in both cell lines, which, in CSCs, was collagen I-dependent and the strongest when treated with phenformin + NAB-PTX. Metabolic disruption in PDAC can be useful both as monotherapy or combined with conventional drugs to more efficiently block tumor growth.
PubMed: 37568684
DOI: 10.3390/cancers15153868 -
BMC Medical Genomics Jul 2023Despite advances in treatment, recurrence and mortality rates from breast cancer (BrCa) continue to rise, clinical effectiveness is limited, and prognosis remains...
BACKGROUND
Despite advances in treatment, recurrence and mortality rates from breast cancer (BrCa) continue to rise, clinical effectiveness is limited, and prognosis remains disappointing, especially for patients with HER2-positive, triple-negative, or advanced breast cancer. Based on cuproptosis-related long noncoding RNAs (CRLs), this study aims to create a predictive signature to assess the prognosis in patients with BrCa.
METHODS
The related CRLs RNA-seq data clinicopathological data were collected from The Cancer Genome Atlas (TCGA) database, and the predictive model was constructed after correlation analysis. Subsequently, we examined and validated connections and changes in the CRLs model with prognostic features (including risk curves, ROC curves and nomograms), pathway and functional enrichment, tumor mutation (TMB), tumor immune dysfunction and exclusion (TIDE) and treatment sensitivity.
RESULTS
A prediction model formula composed of 5 CRLs was obtained, and divided breast cancer patients into high and low risk subgroups according to the obtained risk scores. The results showed that the overall survival (OS) of patients in the high-risk group was lower than that in the low-risk group, and the AUC of all samples at 1, 3 and 5 years were 0.704, 0.668 and 0.647, respectively. It was indicated that CRLs prognostic model could independently predict prognostic indicators of BrCa patients. In addition, analysis of gene set enrichment, immune function, TMB, and TIDE showed that these differentially expressed CRLs had a wealth of related pathways and functions, and might be closely related to immune response and immune microenvironment. Additionally, TP53 was found to have the highest mutation frequency in high-risk group (40%), while PIK3CA was found to have the highest mutation frequency in low-risk group (42%), which might become new targets for targeted therapy. Finally, we compared susceptibility to anticancer agents to identify potential treatment options for breast cancer. Lapatinib, Sunitinib, Phenformin, Idelalisib, Ruxolitinib, Cabozantinib were more sensitive to patients in the low-risk group, while Sorafenib, Vinorelbine, Pyrimethamine were more sensitive to patients in high-risk group, namely, these drugs could potentially be used in the future to treat breast cancer patients grouped according to the risk model.
CONCLUSION
This study identified CRLs associated with breast cancer and provided a tailored tool for predicting prognosis, immune response, and drug sensitivity in patients with BrCa.
Topics: Humans; Female; Breast Neoplasms; RNA, Long Noncoding; Prognosis; Risk Factors; Immunity; Apoptosis; Tumor Microenvironment
PubMed: 37422644
DOI: 10.1186/s12920-023-01590-z -
Clinical Cancer Research : An Official... Sep 2023Oncogene-driven macropinocytosis fuels nutrient scavenging in some cancer types, yet whether this occurs in thyroid cancers with prominent MAPK-ERK and PI3K pathway...
PURPOSE
Oncogene-driven macropinocytosis fuels nutrient scavenging in some cancer types, yet whether this occurs in thyroid cancers with prominent MAPK-ERK and PI3K pathway mutations remains unclear. We hypothesized that understanding links between thyroid cancer signaling and macropinocytosis might uncover new therapeutic strategies.
EXPERIMENTAL DESIGN
Macropinocytosis was assessed across cells derived from papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), non-malignant follicular thyroid, and aggressive anaplastic thyroid cancer (ATC), by imaging fluorescent dextran and serum albumin. The impacts of ectopic BRAFV600E and mutant RAS, genetic PTEN silencing, and inhibitors targeting RET, BRAF, and MEK kinases were quantified. BrafV600E p53-/- ATC tumors in immunocompetent mice were used to measure efficacy of an albumin-drug conjugate comprising microtubule-destabilizing monomethyl auristatin E (MMAE) linked to serum albumin via a cathepsin-cleavable peptide (Alb-vc-MMAE).
RESULTS
FTC and ATC cells showed greater macropinocytosis than non-malignant and PTC cells. ATC tumors accumulated albumin at 8.8% injected dose per gram tissue. Alb-vc-MMAE, but not MMAE alone, reduced tumor size by >90% (P < 0.01). ATC macropinocytosis depended on MAPK/ERK activity and nutrient signaling, and increased by up to 230% with metformin, phenformin, or inhibition of IGF1Ri in monoculture but not in vivo. Macrophages also accumulated albumin and express the cognate IGF1R ligand, IGF1, which reduced ATC responsiveness to IGF1Ri.
CONCLUSIONS
These findings identify regulated oncogene-driven macropinocytosis in thyroid cancers and demonstrate the potential of designing albumin-bound drugs to efficiently treat them.
Topics: Mice; Animals; Phosphatidylinositol 3-Kinases; Mutation; Proto-Oncogene Proteins B-raf; Thyroid Neoplasms; Thyroid Carcinoma, Anaplastic; Oncogenes; Thyroid Cancer, Papillary; Serum Albumin
PubMed: 37289199
DOI: 10.1158/1078-0432.CCR-22-2976