TGFβ<Subscript>1</Subscript> activates c-Jun and Erk1 via α<Subscript>V</Subscript>β<Subscript>6</Subscript> integrin

Transforming growth factor β (TGFβ) plays an important role in animal development and many cellular processes. A variety of cellular functions that are required for tumor metastasis are controlled by integrins, a family of cell adhesion receptors. Overexpression of α_Vβ₆ integrin is associated with lymph node metastasis of gastric carcinomas. It has been demonstrated that a full TGFβ₁ signal requires both α_Vβ₆ integrin and SMAD pathway. TGFβ₁ binds to α_Vβ₆ via the DLXXL motif, a freely accessible amino acid sequence in the mature form of TGFβ₁. Binding of mature TGFβ₁ to α_Vβ₆ leads to immobilization and tyrosine phosphorylation of proteins, which are associated with focal adhesions, a hallmark of integrin-mediated signal transduction. Here, we show that binding of mature TGFβ₁ recruits the mitogen-activated protein kinase kinase kinase 1 (MEKK1), a mediator of c-Jun activation, and the extracellular signaling-regulated kinase-1 (Erk1) to focal adhesions. In addition, the p21-activated kinase 1 (PAK1) is associated with focal adhesions and differentially phosphorylated upon TGFβ₁ stimulation. We conclude that TGFβ₁ activates c-Jun via the MEKK1/p38 MAP kinase pathway and influences cytoskeletal organization. These finding may provide a link between TGFβ₁ and the metastatic behavior of cancers.     

TGFβ<Subscript>1</Subscript> signaling via α<Subscript>V</Subscript>β<Subscript>6</Subscript> integrin

Background

Transforming growth factor β₁ (TGFβ₁) is a potent inhibitor of epithelial cell growth, thus playing an important role in tissue homeostasis. Most carcinoma cells exhibit a reduced sensitivity for TGFβ₁ mediated growth inhibition, suggesting TGFβ₁ participation in the development of these cancers. The tumor suppresor gene DPC4/SMAD4, which is frequently inactivated in carcinoma cells, has been described as a key player in TGFβ₁ mediated growth inhibition. However, some carcinoma cells lacking functional SMAD4 are sensitive to TGFβ₁ induced growth inhibition, thus requiring a SMAD4 independent TGFβ₁ pathway.

Results

Here we report that mature TGFβ₁ is a ligand for the integrin α_Vβ₆, independent of the common integrin binding sequence motif RGD. After TGFβ₁ binds to α_Vβ₆ integrin, different signaling proteins are activated in TGFβ₁-sensitive carcinoma cells, but not in cells that are insensitive to TGFβ₁. Among others, interaction of TGFβ₁ with the α_Vβ₆ integrin resulted in an upregulation of the cell cycle inhibitors p21/WAF1 and p27 leading to growth inhibition in SMAD4 deleted as well as in SMAD4 wildtype carcinoma cells.

Conclusions

Our data provide support for the existence of an alternate TGFβ₁ signaling pathway that is independent of the known SMAD pathway. This alternate pathway involves α_Vβ₆ integrin and the Ras/MAP kinase pathway and does not employ an RGD motif in TGFβ₁-sensitive tumor cells. The combined action of these two pathways seems to be necessary to elicit a complete TGFβ₁ signal.

     

Histamine H<Subscript>4</Subscript> receptor signalling in tongue cancer and its potential role in oral carcinogenesis - a short report

Purpose

Recent reports indicate that histamine and its novel, high-affinity histamine H₄ receptor (H₄R) play a role in carcinogenesis, and thus H₄R signalling has become a focus of increasing interest in the pathogenesis of many cancers. The roles of H₄R in oral epithelial dysplasia (OED) and oral tongue squamous cell carcinoma (OTSCC) are unknown. The purpose of this study was to assess H₄R expression in OTSCC patients and in OTSCC-derived cell lines.

Methods

Biopsies taken from OED, OTSCC and healthy oral mucosa were studied by immunostaining. Primary human oral keratinocytes (HOKs) and two OTSCC-derived cell lines (HSC-3 and SCC-25) were used for the in vitro studies. Quantitative real-time PCR was used to measure oncogene expression in the stimulated HOKs.

Results

We found that H₄R-immunoreactivity was significantly reduced in the OED and OTSCC samples, especially in the samples with higher histopathological grades and noticeably increased mast cell counts. The presence of H₄R in HSC-3 cells had clearly waned, in contrast to the HOKs. Gene expression data indicated that histamine-relevant inflammatory and environmental elements may participate in the regulation of oncogenes.

Conclusions

Our results suggest an association between H₄R and oral carcinogenesis. Furthermore, our findings raise a potential implication of histamine-mediated factors in the regulation of oncogenes, possibly via mast cells, as crucial components of the tumor microenvironment. The identification of new elements that govern oral cancer development is highly relevant for the development of novel therapeutic approaches in OTSCC.

     

15-Deoxy-Δ<Superscript>12,14</Superscript>-prostaglandin J<Subscript>2</Subscript> inhibits G<Subscript>2</Subscript>-M phase progression in human breast cancer cells via the down-regulation of cyclin B1 and survivin expression

The cyclopentenone prostaglandin 15-deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂) exerts a growth inhibitory effect on cancer cells, and this effect is linked to the induction of apoptosis or cell cycle arrest. Induction of apoptosis by 15d-PGJ₂ is associated with the down-regulation of anti-apoptotic proteins. G₀-G₁→S phase progression is inhibited by 15d-PGJ₂ via the degradation of cyclin D1. In this study, we further investigated the mechanism by which 15d-PGJ₂ inhibits cancer cell growth by using the breast cancer cell lines MCF-7 and T-47D. Treatment with 20 μM 15d-PGJ₂ for 72 h completely blocked the growth in both cell lines. However, the proportions of apoptotic MCF-7 and T-47D cells were 21.1% and 40.9%, respectively, indicating that the induction of apoptosis did not appear to fully account for growth inhibition by 15d-PGJ₂. Cell cycle analysis using cells synchronized at the G₀-G₁ or S phase revealed that 15d-PGJ₂ blocked not only G₀-G₁→S phase progression but also G₂-M phase progression. The expression of both cyclins D1 and B1 was decreased by 15d-PGJ₂. Furthermore, 15d-PGJ₂ inhibited aurora-B kinase activity, which coincided with the down-regulation of survivin. Thus, 15d-PGJ₂ induced cell cycle arrest at the G₂-M phase via inhibition of cyclin B1 expression and aurora-B kinase activity. We conclude that survivin may be an important target for 15d-PGJ₂, and its down-regulation may lead to a decrease in aurora-B kinase activity. Naoki Tsuji substantially contributed to this work and should also be considered a first author.     

17β-Estradiol enhances α<Subscript>5</Subscript> integrin subunit gene expression through ERα–Sp1 interaction and reduces cell motility and invasion of ERα-positive breast cancer cells

In breast tumors the expression of estrogen receptor alpha (ERα) is known to be associated with a more favorable prognosis. ERα expression has been reported to reduce the metastatic potential of breast cancer cells. Recently, we have observed that extracellular matrix proteins activate ERα and that both liganded and unliganded receptor modulate cell invasiveness acting at nuclear level. To explain the mechanisms by which ERα regulates cell adhesion, we have evaluated the expression of α₅β₁ integrin, prevalently expressed in stationary cells, in response to 17β-estradiol (E2). Here we show that E2/ERα increases the expression of integrin α₅β₁ through Sp1-mediated binding to a GC-rich region located upstream of an ERE half-site in the 5′ flanking region of the α₅ gene forming a ternary ERα–Sp1-DNA complex. Estrogen responsiveness of the α₅ gene promoter, as observed in HeLa cells, underlies a general mechanism of regulation which is not strictly linked to the cell type. Our data reveal novel insight into the molecular mechanisms sustaining the reduced invasiveness of ERα expressing cells demonstrating that α₅β₁ integrin expression is related to the maintenance of the stationary status of the cells, counteracting E2/ERα capability to enhance breast cancer cell migration and invasion.     

Cooperation of protease-activated receptor 1 and integrin ανβ5 in thrombin-mediated lung cancer cell invasion

Protease-activated receptor 1 (PAR1) and integrins play an important role in thrombin-mediated tumor cell invasion. However, the role of PAR1 and integrin ανβ5 and the relationship between the two receptors in thrombin-induced lung cancer invasion remains unknown. Moreover, the mechanisms through which immobilized thrombin facilitates tumor invasion are poorly understood. In this study, both native and immobilized thrombin promoted lung cancer cell adhesion, migration and extracellular signal-regulated kinase phosphorylation. Integrin ανβ5 is involved in both native and immobilized thrombin-mediated tumor cell invasion; PAR1 had no effect on immobilized thrombin-mediated cell invasion. PAR1 and integrin ανβ5 colocalized on the surface of native thrombin-treated cells. This study suggests that targeting of integrin ανβ5 or the PAR1-integrin ανβ5 complex may present an important therapeutic opportunity to prevent lung cancer invasion.     

Downregulation of <Emphasis Type="Italic">TRPM7</Emphasis> suppressed migration and invasion by regulating epithelial–mesenchymal transition in prostate cancer cells

Metastasis is a leading cause of death in patients with prostate cancer (PCa). Transient receptor potential channel 7 (TRPM7) functions as a Mg²⁺/Ca²⁺-permeable channel as well as a protein kinase that regulate various cellular processes including cell adhesion, migration and survival. However, the function of TRPM7 in metastasis of PCa remains largely unknown. Microarray analysis suggested that calcium signaling pathway was significantly altered in metastatic PCa tissues, compared with benign prostatic hyperplasia tissues. Bioinformatics analysis using microarray data and database for annotation, visualization and integrated discovery database revealed altered genes involved in calcium signaling pathway were significantly upregulated in TRPM7 deficiency PCa cells, which was also confirmed by experimental verification. Therefore, we aim to investigate the role of TRPM7 in human PCa cell migration and invasion as well as the underlying mechanisms. We observed that TRPM7 was upregulated in PCa cells and tissues compared with prostate hyperplasia cells and tissues. Further investigations suggested that TRPM7 deficiency suppressed migration and invasion of distinct PCa cell lines while overexpression of TRPM7 increased migration of PCa cells. In addition, knockdown of TRPM7 in PCa cells reversed the epithelial–mesenchymal transition (EMT) status, accompanied by downregulation of MMPs and upregulation of E-cadherin. Taken together, our study indicated that downregulation of TRPM7 could inhibit migration and invasion via reversing EMT status in PCa cells.     

1 α-Hydroxyvitamin D<Subscript>2</Subscript> inhibits growth of human neuroblastoma

Neuroblastoma is the most common extracranial solid tumor in childhood. The poor outcomes of patients with high-risk neuroblastoma have encouraged the search for new therapies. In the current study, the effect of the vitamin D analog 1α-hydroxyvitamin D₂ (1α-OH-D₂, doxercalciferol) was assessed in a mouse xenograft model of human neuroblastoma. Vitamin D receptor (VDR) expression levels in seven neuroblastoma cell lines were compared using real-time PCR. SK-N-AS cells, which express relatively high levels of VDR, were injected into the flanks of 60 mice. The mice were treated daily via oral gavage for 5 weeks with vehicle (control), 0.15 μg, or 0.3 μg of 1α-OH-D₂. The animals were then euthanized, and tumors, sera, and kidneys were collected and analyzed. End tumor volumes were significantly smaller in both the 0.15 μg group (712.07 mm³, P = 0.0121) and 0.3 μg group (772.97 mm³, P = 0.0209) when compared to controls (1,681.75 mm³). In terms of toxicity, serum calcium levels were increased but mortality was minimal in both treatment groups. These results were similar to those previously described in the transgenic (LHβ-Tag) and human xenograft (Y-79) models of retinoblastoma, a related tumor. In vitro cell viability studies of SK-N-AS and NGP cells, which represent two major human neuroblastoma subtypes that differ in their genetic abnormalities as well as their VDR expression levels, show that both are sensitive to calcitriol, the active metabolite of vitamin D₃. In conclusion, the present study shows that 1α-OH-D₂ can inhibit human neuroblastoma growth in vivo with relatively low toxicity. The safety of 1α-OH-D₂ has been extensively studied; the drug is FDA-approved for the treatment of adult kidney patients, and Phase I/II trials have been conducted in adult oncology patients. There should not be major obstacles to starting Phase I and II clinical trials with this drug in pediatric patients with high-risk neuroblastoma.     

Radiolabeled F(ab′)<Subscript>2</Subscript>-cetuximab for theranostic purposes in colorectal and skin tumor-bearing mice models

Purpose

This study aimed to investigate theranostic strategies in colorectal and skin cancer based on fragments of cetuximab, an anti-EGFR mAb, labeled with radionuclide with imaging and therapeutic properties, ¹¹¹In and ¹⁷⁷Lu, respectively.

Methods

We designed F(ab′)₂-fragments of cetuximab radiolabeled with ¹¹¹In and ¹⁷⁷Lu. ¹¹¹In-F(ab′)₂-cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of ¹¹¹In-F(ab′)₂-cetuximab to assess therapy efficacy was performed on BalbC nude mice bearing colorectal tumors receiving 17-DMAG, an HSP90 inhibitor. Therapeutic efficacy of the radioimmunotherapy based on ¹⁷⁷Lu-F(ab′)₂-cetuximab was evaluated in SWISS nude mice bearing A431 tumors.

Results

Radiolabeling procedure did not change F(ab′)₂-cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. ¹¹¹In-DOTAGA-F(ab′)₂-cetuximab exhibited a peak tumor uptake at 24 h post-injection and showed a high tumor specificity determined by a significant decrease in tumor uptake after the addition of an excess of unlabeled-DOTAGA-F(ab′)₂-cetuximab. SPECT imaging of ¹¹¹In-DOTAGA-F(ab′)₂-cetuximab allowed an accurate evaluation of tumor growth and successfully predicted the decrease in tumor growth induced by 17-DMAG. Finally, ¹⁷⁷Lu-DOTAGA-F(ab′)₂-cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq doses.

Conclusions

¹¹¹In-DOTAGA-F(ab′)₂-cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. ¹⁷⁷Lu-DOTAGA-F(ab′)₂-cetuximab is an interesting theranostic tool allowing therapy and imaging.

     

Activin B induces human endometrial cancer cell adhesion,migration and invasion by up-regulating integrin β3 via SMAD2/3 signaling

Endometrial cancer is the fourth most common female cancer and the most common gynecological malignancy. Although it comprises only ~10% of all endometrial cancers, the serous histological subtype accounts for ~40% of deaths due to its aggressive behavior and propensity to metastasize. Histopathological studies suggest that elevated expression of activin/inhibin βB subunit is associated with reduced survival in non-endometrioid endometrial cancers (type II, mostly serous). However, little is known about the specific roles and mechanisms of activin (βB dimer) in serous endometrial cancer growth and progression. In the present study, we examined the biological functions of activin B in type II endometrial cancer cell lines, HEC-1B and KLE. Our results demonstrate that treatment with activin B increases cell migration, invasion and adhesion to vitronectin, but does not affect cell viability. Moreover, we show that activin B treatment increases integrin β3 mRNA and protein levels via SMAD2/3-SMAD4 signaling. Importantly, siRNA knockdown studies revealed that integrin β3 is required for basal and activin B-induced cell migration, invasion and adhesion. Our results suggest that activin B-SMAD2/3-integrin β3 signaling could contribute to poor patient survival by promoting the invasion and/or metastasis of type II endometrial cancers.     

Tumour-suppressive microRNA-29s inhibit cancer cell migration and invasion by targeting laminin–integrin signalling in head and neck squamous cell carcinoma

Background:

Our recent studies of microRNA (miRNA) expression signatures demonstrated that microRNA-29s (miR-29s; miR-29a/b/c) were significantly downregulated in head and neck squamous cell carcinoma (HNSCC) and were putative tumour-suppressive miRNAs in human cancers. Our aim in this study was to investigate the functional significance of miR-29s in cancer cells and to identify novel miR-29s-mediated cancer pathways and responsible genes in HNSCC oncogenesis and metastasis.

Methods:

Gain-of-function studies using mature miR-29s were performed to investigate cell proliferation, migration and invasion in two HNSCC cell lines (SAS and FaDu). To identify miR-29s-mediated molecular pathways and targets, we utilised gene expression analysis and in silico database analysis. Loss-of-function assays were performed to investigate the functional significance of miR-29s target genes.

Results:

Restoration of miR-29s in SAS and FaDu cell lines revealed significant inhibition of cancer cell migration and invasion. Gene expression data and in silico analysis demonstrated that miR-29s modulated the focal adhesion pathway. Moreover, laminin γ2 (LAMC2) and α6 integrin (ITGA6) genes were candidate targets of the regulation of miR-29s. Luciferase reporter assays showed that miR-29s directly regulated LAMC2 and ITGA6. Silencing of LAMC2 and ITGA6 genes significantly inhibited cell migration and invasion in cancer cells.

Conclusion:

Downregulation of miR-29s was a frequent event in HNSCC. The miR-29s acted as tumour suppressors and directly targeted laminin–integrin signalling. Recognition of tumour-suppressive miRNA-mediated cancer pathways provides new insights into the potential mechanisms of HNSCC oncogenesis and metastasis and suggests novel therapeutic strategies for the disease.     

Liprin-α1 regulates breast cancer cell invasion by affecting cell motility, invadopodia and extracellular matrix degradation

Migration of cells and degradation of the extracellular matrix (ECM) are required for efficient tumor cell invasion, but the underlying molecular mechanisms are only partially known. The PPFIA1 gene for liprin-α1 is frequently amplified in human breast cancers. We recently demonstrated that liprin-α1 is an important regulator of cell edge dynamics during motility. We show, herein, that the liprin-α1 protein is highly expressed in human breast tumors. Functional analysis shows that liprin-α1 is specifically required for the migration and invasion of highly invasive human breast cancer MDA-MB-231 cells. We used time-lapse analysis to demonstrate defects in the motility of liprin-α1-depleted cells that include a striking instability of the lamellipodia. Liprin-α1 levels altered by either RNA interference or overexpression affected also cell spreading and the number of invadopodia per cell, but not the density of invadopodia per unit of surface area. On the other hand, silencing of liprin-α1 inhibited the degradation of the ECM, whereas its overexpression enhanced degradation, resulting in significant negative or positive effects, respectively, on the area of degradation per invadopodium. Transfection of fluorescent-labeled cortactin revealed that depletion of liprin-α1 also affected the assembly and disassembly of invadopodia, with decrease of their lifetime. Our results strongly support a novel important role of liprin-α1 in the regulation of human tumor cell invasion.     

IL-13 regulates cancer invasion and metastasis through IL-13Rα2 via ERK/AP-1 pathway in mouse model of human ovarian cancer

Previously, we have demonstrated that a variety of human cancers including the ovarian cancer express IL-13Rα2, a high affinity receptor for IL-13. Herein, we have examined if IL-13 regulates invasion and metastasis of ovarian cancer through IL-13Rα2 in vitro and in vivo in animal models of human ovarian cancer. We tested cell invasion and protease activity in IL-13Rα2-overexpressing and IL-13Rα2-negative ovarian tumor cell lines. IL-13 treatment significantly augmented both cell invasion and enzyme activities in only IL-13Rα2-positive cells but not in IL-13Rα2-negative cells in vitro. Mechanistically, IL-13 enhanced ERK1/2, AP-1 and MMP activities only in IL-13Rα2-positive cells but not in IL-13Rα2-negative cells. In contrast, other signaling pathways such as IRS1/2, PI3K and AKT do not seem to be involved in IL-13 induced signaling in ovarian cancer cell lines. Highly specific inhibitors for MMP and AP-1 efficiently inhibited both invasion and protease activities without impacting the basal level invasion and protease activities in vitro. In orthotopic animal model of human ovarian cancer, IL-13Rα2-positive tumors metastasized to lymph nodes and peritoneum earlier than IL-13Rα2-negative tumors. Interestingly, the IL-13Rα2-positive tumor bearing mice died earlier than mice with IL-13Rα2-negative tumor. Intraperitoneal injection of IL-13 further shortened survival of IL-13Rα2-positive tumor bearing mice compared to IL-13Rα2-negative tumor mice. IL-13Rα2-positive tumors and lymph node metastasis expressed higher levels of MMPs and higher ERK1/2 activation compared to IL-13Rα2-negative tumors. Taken together, IL-13Rα2 is involved in cancer metastasis through activation of ERK/AP-1 and that targeting IL-13Rα2 might not only directly kill primary tumors but also prevent cancer metastasis.     

Ambient PM<Subscript>2.5</Subscript> air pollution exposure and hepatocellular carcinoma incidence in the United States

Purpose

To conduct the first epidemiologic study prospectively examining the association between particulate matter air pollution?<?2.5 µm in diameter (PM_2.5) exposure and hepatocellular carcinoma (HCC) risk in the U.S.

Methods

Surveillance, Epidemiology, and End Results (SEER) provided information on HCC cases diagnosed between 2000 and 2014 from 16 population-based cancer registries across the U.S. Ambient PM_2.5 exposure was estimated by linking the SEER county with a spatial PM_2.5 model using a geographic information system. Poisson regression with robust variance estimation was used to calculate incidence rate ratios and 95% confidence intervals (CIs) for the association between ambient PM_2.5 exposure per 10 µg/m³ increase and HCC risk adjusting for individual-level age at diagnosis, sex, race, year of diagnosis, SEER registry, and county-level information on health conditions, lifestyle, demographic, socioeconomic, and environmental factors.

Results

Higher levels of ambient PM_2.5 exposure were associated with a statistically significant increased risk for HCC (n?=?56,245 cases; adjusted IRR per 10 µg/m³ increase?=?1.26, 95% CI 1.08, 1.47; p?<?0.01).

Conclusions

If confirmed in studies with individual-level PM_2.5 exposure and risk factor information, these results suggest that ambient PM_2.5 exposure may be a risk factor for HCC in the U.S.

     

Metalloprotease-dependent activation of EGFR modulates CD44<Superscript>+</Superscript>/CD24<Superscript>−</Superscript> populations in triple negative breast cancer cells through the MEK/ERK pathway

Purpose

Objective cosmetic analysis is important to evaluate the cosmetic outcome after breast surgery or breast radiotherapy. For this purpose, we aimed to improve our recently developed objective scoring software, the Breast Analyzing Tool (BAT^®).

Methods

A questionnaire about important factors for breast symmetry was handed out to ten experts (surgeons) and eight non-experts (students). Using these factors, the first-generation BAT^® software formula has been modified and the breast symmetry index (BSI) from 129 women after breast surgery has been calculated by the first author with this new BAT^® formula. The resulting BSI values of these 129 breast cancer patients were then correlated with subjective symmetry scores from the 18 observers using the Harris scale. The BSI of ten images was also calculated from five observers different from the first author to calculate inter-rater reliability. In a second phase, the new BAT^® formula was validated and correlated with subjective scores of additional 50 women after breast surgery.

Results

The inter-rater reliability analysis of the objective evaluation by the BAT^® from five individuals showed an ICC of 0.992 with almost no difference between different observers. All subjective scores of 50 patients correlated with the modified BSI score with a high Pearson correlation coefficient of 0.909 (p < .001) which was better compared to the old software (r = 0.769; p < .001).

Conclusions

The modified BAT^® software improves the correlation between subjective and objective BSI values, and may be a new standard for trials evaluating breast symmetry.

     

Hypoxia induces a lipogenic cancer cell phenotype via HIF1α-dependent and -independent pathways

The biochemistry of cancer cells diverges significantly from normal cells as a result of a comprehensive reprogramming of metabolic pathways. A major factor influencing cancer metabolism is hypoxia, which is mediated by HIF1α and HIF2α. HIF1α represents one of the principal regulators of metabolism and energetic balance in cancer cells through its regulation of glycolysis, glycogen synthesis, Krebs cycle and the pentose phosphate shunt. However, less is known about the role of HIF1α in modulating lipid metabolism. Lipids serve cancer cells to provide molecules acting as oncogenic signals, energetic reserve, precursors for new membrane synthesis and to balance redox biological reactions. To study the role of HIF1α in these processes, we used HCT116 colorectal cancer cells expressing endogenous HIF1α and cells in which the hif1α gene was deleted to characterize HIF1α-dependent and independent effects on hypoxia regulated lipid metabolites. Untargeted metabolomics integrated with proteomics revealed that hypoxia induced many changes in lipids metabolites. Enzymatic steps in fatty acid synthesis and the Kennedy pathway were modified in a HIF1α-dependent fashion. Palmitate, stearate, PLD3 and PAFC16 were regulated in a HIF-independent manner. Our results demonstrate the impact of hypoxia on lipid metabolites, of which a distinct subset is regulated by HIF1α.