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PKCz restrains cancer cell transformation by inhibiting nutrient stress-induced metabolic reprogramming

ABSTRACT: Tumor cells utilize the so-called Warburg effect to allow for rapid proliferation with glucose as the main nutrient. We show here that, although PKCz is critical for that effect, its deficiency promotes the plasticity necessary for nutrient-stressed cancer cells to reprogram their metabolism to utilize glutamine through the serine biosynthetic pathway, empowering them to survive and proliferate in the absence of glucose. We show that PKCz deficiency enhances glutamine utilization and expression of two key enzymes of the pathway, PGHDGH and PSAT1, in cells cultured in the absence of glucose. The loss of PKCz in mice results in enhanced intestinal tumorigenesis and increased levels of these two metabolic enzymes, while patients with low levels of PKCz have a poor prognosis. Taken together, this suggests that PKCz is a critical metabolic tumor suppressor.

ORGANISM(S): Homo sapiens

PROVIDER: GSE42186 | GEO | 2013/01/01

SECONDARY ACCESSION(S): PRJNA179262

REPOSITORIES: GEO

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PKCz restrains cancer cell transformation by inhibiting nutrient stress-induced metabolic reprogramming

Project description:Tumor cells utilize the so-called Warburg effect to allow for rapid proliferation with glucose as the main nutrient. We show here that, although PKCz is critical for that effect, its deficiency promotes the plasticity necessary for nutrient-stressed cancer cells to reprogram their metabolism to utilize glutamine through the serine biosynthetic pathway, empowering them to survive and proliferate in the absence of glucose. We show that PKCz deficiency enhances glutamine utilization and expression of two key enzymes of the pathway, PGHDGH and PSAT1, in cells cultured in the absence of glucose. The loss of PKCz in mice results in enhanced intestinal tumorigenesis and increased levels of these two metabolic enzymes, while patients with low levels of PKCz have a poor prognosis. Taken together, this suggests that PKCz is a critical metabolic tumor suppressor. SW480 cells were infected with lentivirus expressing PKCz RNA interference (shPKCz) and a control lentivirus (shNT). The elimination of endogenous PKCz with shPKCz transfection was >90% efficient. Cells transfected with shNT had unaltered levels of PKCz. To mimic the conditions of nutrient stress to which tumor cells are normally exposed, both cell types were initially seeded in DMEM with 10% FBS, and cultured without subsequent further media changes, which led to nutrient exhaustion over time. Total RNA was harvested from three independent biological replicates for shPKCz and shNT transfected cells.

2013-01-01 | E-GEOD-42186 | biostudies-arrayexpress

The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade

Project description:Cultured cancer cells frequently rely on the consumption of glutamine and its subsequent hydrolysis to glutamate by the mitochondrial enzyme glutaminase (GLS). However, this metabolic addiction can be lost in the tumor microenvironment (TME), rendering GLS inhibitors ineffective in the clinic. Here, we show that seemingly glutamine-addicted breast cancer cells ultimately adapt to chronic glutamine starvation, or targeted GLS inhibition, via the AMPK-mediated upregulation of the serine synthesis pathway (SSP). In this context, the key product of the SSP is not serine itself, but a-ketoglutarate (a-KG). Mechanistically, we find that the phylogenetically distinct transaminase phosphoserine aminotransferase 1 (PSAT1) has a unique capacity for sustained a-KG production when glutamate is severely depleted. Breast cancer cells with intrinsic or acquired resistance to glutamine starvation or GLS inhibition are highly dependent on SSP-supplied a-KG. Accordingly, pharmacological disruption of the SSP prevents adaptation to glutamine blockade, yielding a potent drug synergism that abolishes breast tumor growth in vivo. These findings highlight how metabolic redundancy can be context dependent, with the catalytic properties of different metabolic enzymes that act on the same substrate determining which pathways can support tumor growth in a particular nutrient environment. This in turn has practical consequences for therapies targeting cancer metabolism.

2024-07-05 | GSE263696 | GEO

Gene expression analysis of H1299 cells in response to the presence or absence of glutamine or glucose

Project description:By a transcriptome analysis using RNA sequencing in H1299 cells, a non-small cell lung cancer cell line (NSCLC), we determined the response of lipogenic genes to absence vs. presence of glutamine (Gln) or glucose (Gluc). We found that neither glutamine nor glucose alone was able to activate the expression of genes regulating fatty acid and cholesterol synthesis, and uptake, including SREBF1, SREBF2, ACLY, ACACA, FASN, SCD1, HMGCR and LDLR, as compared to absence of both. And, activation of lipogenic genes required the presence of both glutamine and glucose, but SCAP gene expression was not affected by either glutamine or glucose. The RNA sequencing analysis in H1299 cells also confirmed that ammonia, similarly to glutamine, significantly activated the expression of genes controlling the fatty acid and cholesterol synthesis pathways as compared to glucose alone. This study detemines the intrinsic molecular connection between glutamine, glucose and lipid synthesis.

2022-04-30 | GSE199089 | GEO

Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer [mouse]

Project description:Tumor cells rely on glutamine to fulfill their metabolic demands and sustain proliferation. The elevated consumption of glutamine can lead to intratumoral nutrient depletion, causing metabolic stress that has the potential to impact tumor progression. Here, we show that nutrient stress caused by glutamine deprivation leads to the induction of epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, we demonstrate that glutamine deficiency regulates EMT through the upregulation of the EMT master regulator Slug, a process that is dependent on both MEK/ERK signaling and ATF4. We find that Slug is required in PDAC cells for glutamine deprivation-induced EMT, cell motility and nutrient stress survival. Importantly, we decipher that Slug is associated with nutrient stress in PDAC tumors and is required for metastasis. These results delineate a novel role for Slug in the nutrient stress response and provide insight into how nutrient depletion might influence PDAC progression.

2020-05-20 | GSE150874 | GEO

Glutamine depletion regulates Slug to promote EMT and metastasis in pancreatic cancer [human]

2020-05-20 | GSE150873 | GEO

Expression data from TH17 cells cultured in the presence or absence of glutamine

Project description:T cell fate and function is closely related to nutrient uptake and utilization. Here we demonstrate that glutamine deprivation switch Th17 cells to Treg cells in a time and dose dependent manner. The finding highlight the critical role of glutamine in T cell fate determination through a metabolic-epigenetic axis. We performed microarrays to explore the gene expression pattern of TH17 cells in the presence or absence of glutamine.

2024-02-09 | GSE166430 | GEO

PSAT1 mediated changes in gene expression in EGF-stimulated lung cancer

Project description:In addition to supporting increased cellular metabolism for untethered neoplastic growth, recent reports have indicated that certain metabolic enzymes may exhibit alternative functions in human cancers. Despite the ability to import serine from the microenvironment, lung tumors significantly elevate expression of biosynthetic enzymes responsible for the de novo production of serine, notably phosphoserine aminotransferase 1 (PSAT1). Highlighting the relevance of PSAT1 in lung cancer, patients with increased expression demonstrated poorer overall survival, so characterizing its role in lung tumor progression may ultimately identify different therapeutic strategies targeting this disease. Our preliminary studies now demonstrate a potential alternative function, beyond serine synthesis, of PSAT1 in lung tumor cells. Specifically, we found that PSAT1 localizes to the nucleus upon epidermal growth factor stimulation [via activating EGFR mutation (PC9, inhibited by the EGFR-mutant specific inhibitor, Erlotinib) or EGF stimulation (A549, EGFR-WT)] and regulates the nuclear import of pyruvate kinase M2 (PKM2). Importantly, nuclear PKM2 has been demonstrated to directly phosphorylate histones and modify gene transcription. In further support of this functional interaction, within yeast, PKM2 association with serine synthetic enzymes resulted in pervasive chromatin remodeling and alteration in global gene expression. Therefore, our objective in this proposal is to define gene signatures promoted by PSAT1-mediated nuclear PKM2 translocation in response to EGF-signaling in human lung cancer cells.

2024-04-23 | GSE173270 | GEO

A role for p53 in the adaptation to glutamine starvation through the expression of Slc1a3

Project description:Numerous mechanisms to support cells under conditions of transient nutrient starvation have been described. The tumor suppressor protein p53 can contribute to the adaptation of cells to metabolic stress through various mechanisms that may help cancer cell survival in nutrient limiting conditions. We show here that p53 helps cancer cells to survive glutamine starvation by promoting the expression of SLC1A3, an aspartate/glutamate transporter that allows the utilization of aspartate to support cells in the absence of extracellular glutamine. Under glutamine deprivation, SLC1A3 expression maintains electron transport chain and tricarboxylic acid cycle activity, promoting de novo glutamate, glutamine and nucleotide synthesis to rescue cell viability. Tumor cells with high levels of SLC1A3 expression are resistant to glutamine starvation and SLC1A3 depletion retards the growth of these cells in vitro and in vivo, suggesting a therapeutic potential for SLC1A3 inhibition.

2018-06-28 | GSE116087 | GEO

Cell polarity proteins promote macropinocytosis in response to metabolic stress

Project description:Macropinocytosis has emerged as a nutrient-scavenging pathway that cancer cells exploit to survive the nutrient-deprived conditions of the tumor microenvironment. Cancer cells are especially reliant on glutamine for their survival, and in pancreatic ductal adenocarcinoma (PDAC) cells, glutamine deficiency can enhance the stimulation of macropinocytosis, allowing the cells to escape metabolic stress through the production of extracellular-protein-derived amino acids. Here, we identify the atypical protein kinase C (aPKC) enzymes, PKC and PKCas novel regulators of macropinocytosis. In normal epithelial cells, aPKCs are known to regulate cell polarity in association with the scaffold proteins Par3 and Par6, controlling the function of several targets, including the Par1 kinases. In PDAC cells, we identify that each of these cell polarity proteins are required for glutamine stress-induced macropinocytosis. Mechanistically, we find that the aPKCs are regulated by EGFR signaling or by the transcription factor CREM to promote the relocation of Par3 to microtubules, facilitating macropinocytosis in a dynein-dependent manner. Importantly, we determine that cell fitness impairment caused by aPKC depletion is rescued by the restoration of macropinocytosis and that aPKCs support PDAC growth in vivo. These results identify a previously unappreciated role for cell polarity proteins in the regulation of macropinocytosis and provide a better understanding of the mechanistic underpinnings that control macropinocytic uptake in the context of metabolic stress.

2024-10-22 | GSE276007 | GEO

Glutamine is critical for the maintenance of Type 1 Conventional Dendritic cells in normal tissue and the tumor microenvironment.

Project description:Proliferating tumor cells take up glutamine for anabolic processes, engendering glutamine deficiency in the tumor microenvironment. How this might impact immune cells is not well understood. Using multiple mouse models of soft tissue sarcomas, glutamine antagonists, as well as genetic and pharmacological inhibition of glutamine utilization, we found that the number and frequency of conventional dendritic cells (cDC) is dependent on microenvironmental glutamine levels. cDCs comprise two distinct subsets – cDC1s and cDC2s, with the former subset playing a critical role in antigen cross-presentation and tumor immunity. While both subsets show dependence on glutamine, cDC1s are particularly sensitive. Notably, glutamine antagonism did not reduce the frequency of DC precursors but decreased the proliferation and survival of cDC1s. Further studies suggest a role of the nutrient sensing mTOR signaling pathway in this process. Taken together, these findings uncover glutamine dependence of cDC1s that is coopted by tumors to escape immune responses.

2024-10-16 | GSE279324 | GEO

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