bims-stacyt 2022-05-15 papers

bims-stacyt

Biomed News

on Paracrine crosstalk between cancer and the organism

Issue of 2022‒05‒15
eight papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

TGF-β1 induced autophagy in cancer associated fibroblasts during hypoxia contributes EMT and glycolysis via MCT4 upregulation.
Exploring the Role of Metabolites in Cancer and the Associated Nerve Crosstalk.
TLR4 Promotes ER stress and Unfolded Protein Response in Hypertension-Induced Kidney Injury.
Common signaling principles and interconnectivity in the ISR-UPR networks.
RIP3 translocation into Mitochondria promotes Mitofilin degradation to increase inflammation and kidney injury after renal ischemia/reperfusion.
Targeting Hypoxia-Adenosinergic Signaling to Enable Effective Anti-Tumor Responses by Reprogramming the Immunosuppressive Tumor Microenvironment.
TRAP1 regulates the response of colorectal cancer cells to hypoxia and inhibits ribosome biogenesis under conditions of oxygen deprivation.
Sestrin2 in cancer: a foe or a friend?

Exp Cell Res. 2022 May 10. pii: S0014-4827(22)00188-4. [Epub ahead of print] 113195

TGF-β1 induced autophagy in cancer associated fibroblasts during hypoxia contributes EMT and glycolysis via MCT4 upregulation.

Bikash Chandra Jena, Chandan Kanta Das, Indranil Banerjee, Deblina Bharadwaj, Ranabir Majumder, Subhayan Das, Angana Biswas, Moumita Kundu, Pritam Kumar Roy, Chanakya Nath Kundu, Mahitosh Mandal.

  The Transforming growth factor-β1(TGF- β1) in the tumor microenvironment(TME) is the major cytokine that acts as a mediator of tumor-stroma crosstalk, which in fact has a dual role in either promoting or suppressing tumor development. The cancer-associated fibroblasts (CAFs) are the major cell types in the TME, and the interaction with most of the epithelial cancers is the prime reason for cancer survival. However, the molecular mechanisms, associated with the TGF- β1 induced tumor promotion through tumor-CAF crosstalk are not well understood. In the Reverse Warburg effect, CAFs feed the adjacent cancer cells by lactate produced during the aerobic glycolysis. We hypothesized that the monocarboxylate transporter, MCT4 which is implicated in lactate efflux from the CAFs, must be overexpressed in the CAFs. Contextually, to explore the role of TGF- β1 in the hypoxia-induced autophagy in CAFs, we treated CoCl2 and external TGF- β1 to the human dermal fibroblasts and L929 murine fibroblasts. We demonstrated that hypoxia accelerated the TGF- β1 signaling and subsequent transformation of normal fibroblasts to CAFs. Moreover, we elucidated that synergistic induction of autophagy by hypoxia and TGF- β1 upregulate the aerobic glycolysis and MCT4 expression in CAFs. Furthermore, we showed a positive correlation between glucose consumption and MCT4 expression in the CAFs. Autophagy was also found to be involved in the EMT in hypoxic CAFs. Collectively, these findings reveal the unappreciated role of autophagy in TME, which enhances the CAF transformation and that promotes tumor migration and metastasis via the reverse Warburg effect.

Keywords:  Chemoresistance; Cocl2; MCT4; Reverse warburg effect; TGF-β/Smad signaling; Tumor-stroma crosstalk

DOI:  https://doi.org/10.1016/j.yexcr.2022.113195
Nutrients. 2022 Apr 21. pii: 1722. [Epub ahead of print]14(9):

Exploring the Role of Metabolites in Cancer and the Associated Nerve Crosstalk.

Inah Gu, Emory Gregory, Casey Atwood, Sun-Ok Lee, Young Hye Song.

  Since Otto Warburg's first report on the increased uptake of glucose and lactate release by cancer cells, dysregulated metabolism has been acknowledged as a hallmark of cancer that promotes proliferation and metastasis. Over the last century, studies have shown that cancer metabolism is complex, and by-products of glucose and glutamine catabolism induce a cascade of both pro- and antitumorigenic processes. Some vitamins, which have traditionally been praised for preventing and inhibiting the proliferation of cancer cells, have also been proven to cause cancer progression in a dose-dependent manner. Importantly, recent findings have shown that the nervous system is a key player in tumor growth and metastasis via perineural invasion and tumor innervation. However, the link between cancer-nerve crosstalk and tumor metabolism remains unclear. Here, we discuss the roles of relatively underappreciated metabolites in cancer-nerve crosstalk, including lactate, vitamins, and amino acids, and propose the investigation of nutrients in cancer-nerve crosstalk based on their tumorigenicity and neuroregulatory capabilities. Continued research into the metabolic regulation of cancer-nerve crosstalk will provide a more comprehensive understanding of tumor mechanisms and may lead to the identification of potential targets for future cancer therapies.

Keywords:  amino acid metabolism; cancer; cancer–nerve crosstalk; lactate; metabolites; perineural invasion; tumor innervation; vitamins

DOI:  https://doi.org/10.3390/nu14091722
FASEB J. 2022 May;36 Suppl 1

TLR4 Promotes ER stress and Unfolded Protein Response in Hypertension-Induced Kidney Injury.

Sathnur Pushpakumar, Subir Kumar Juin, Jaden Whitehead, Utpal Sen.

Hypertension is the second leading cause of chronic kidney injury in the world. Endoplasmic reticulum (ER) is an important cell organelle that is involved in the synthesis, folding, and modification of various proteins to maintain homeostasis. ER stress is reported in hypertension-induced damage of kidney, heart and brain. Further, TLR4 activation and signaling is linked to the development and progression of hypertension induced damage in various organs; however, the interplay between TLR4 and ER stress in renal pathology remains unknown. In the present study, we investigated whether TLR4 activation contributes to renal ER stress and inflammation in Angiotensin-II (Ang-II) induced hypertension and whether TLR4 deficiency protects the kidney by suppressing ER stress. C3H/HeouJ (Normal TLR4, TLR4N) and C3H/HeJ (Dysfunctional TLR4, TLR4M) aged 12-14 weeks were treated with Ang-II (1000 ng/Kg/min. x 28 days) using osmotic pumps. We found renal function was impaired in TLR4N mice compared to TLR4M. The expression of ER stress markers (ATF6, p-IRE1α and p-PERK), renal inflammation (TNFα, IL-1β, CCL2) and transcription factor p-NFkB was upregulated in TLR4N kidneys compared to TLR4M. Further, ER stress in TLR4N mice was associated with mRNA changes in GRP78, sXBP1, ATF4, CHOP genes that are involved in unfolded protein response. In TLR4N mice, renal inflammation was predominant in the tubular area and ER stress was observed in both glomerular and tubular area. TLR4M mice showed reduced ER stress and inflammation in the kidney. Taken together, our results suggest significant interaction between TLR4 and ER stress that may act as an obligatory step in mediating renal inflammation and damage, and TLR4 deficiency attenuates injury by regulating ER stress and unfolded protein response in Ang-II-induced hypertension.

DOI: https://doi.org/10.1096/fasebj.2022.36.S1.R3963
FASEB J. 2022 May;36 Suppl 1

Common signaling principles and interconnectivity in the ISR-UPR networks.

Diego Acosta-Alvear.

The integrated stress response (ISR) and the unfolded protein response (UPR) are conserved signaling networks governed by stress sensor kinases. Four ISR sensor kinases, GCN2, HRI, PERK, and PKR, phosphorylate eIF2α in response to multiple stresses, leading to a global protein synthesis shutdown coupled to the translation of select mRNAs, which results in an adaptive remodeling of the proteome. Besides PERK, which the ISR and the UPR share, the UPR relies on two additional ER stress sensors, the kinase/RNase IRE1 and the membrane-tethered transcription factor ATF6, to induce adaptive signaling programs that reinstate ER homeostasis. However, if the stress is unrelenting, both the ISR and the UPR can switch to drive cell death. The mechanistic commonalities and crosstalk between the ISR and UPR remain an active area of investigation. In this talk, I will share new results that support common signaling principles of the ISR and UPR sensor kinases and reveal a new layer of communication between the ISR and the UPR. Specifically, we found that dynamic clustering is a prominent feature of PKR activation reminiscent of the high-order assemblies of IRE1 and PERK observed during ER stress. Surprisingly, PKR clusters excluded eIF2α, and mutations in PKR that disrupt cluster assembly enhanced eIF2α phosphorylation, suggesting that PKR clusters act as enzyme sinks that control enzyme-substrate interactions by limiting PKR-eIF2α encounters. Moreover, stress-free activation of PKR induced a master cell death program dependent on ISR-driven expression of DR5 (death receptor 5), as occurs during unmitigable ER stress. Remarkably, stress-free activation of the ISR selectively activated IRE1 independent of sensing unfolded proteins in the ER lumen, and treatment with the small-molecule ISR inhibitor ISRIB reversed it. Our data provide new mechanistic insights into two fundamental aspects of stress sensor kinase signaling: (1) dynamic clustering of stress sensors may provide the means to fine-tune stress responses, and (2) the ISR selectively activates IRE1, thus coupling the ISR and the UPR outside their common node PERK.

DOI: https://doi.org/10.1096/fasebj.2022.36.S1.0I138
FASEB J. 2022 May;36 Suppl 1

RIP3 translocation into Mitochondria promotes Mitofilin degradation to increase inflammation and kidney injury after renal ischemia/reperfusion.

Yanshen C Feng, Derrick Draeger, Jean C Bopassa.

BACKGROUND: . Acute kidney injury (AKI) is an independent risk factor for mortality and morbidity. Inflammation is now believed to play a major role in the pathophysiology of AKI. Receptor-interacting protein kinase 3 (RIP3) is a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases. RIP3 is a regulator of both programmed necrosis/necroptosis, an inflammatory form of cell death observed in pathogen-induced and sterile inflammation, and TNFα-induced apoptosis. In the induction of necroptosis, RIP3 is a major component of the tumor necrosis factor (TNF) receptor-I signaling complex which through additional interactions with (RIP1) and pseudokinase mixed lineage kinase domain-like protein (MLKL) forms the necrosome. More recently, RIP3 activity was found to promote sepsis-induced AKI via mitochondrial dysfunction. Since I/R injury triggers numerous pathological changes, including apoptosis, oxidative stress, and inflammation, suggesting a role of mitochondrial function in RIP3-dependent I/R injury.OBJECTIVE: We investigated whether RIP3 translocates into mitochondria in response to ischemia/reperfusion (I/R) to interact with Mitofilin and promote mitochondria damage that facilitates mtDNA release into the cytosol. We postulated that release of mtDNA activates cGAS/STING pathway leading to increased nuclear transcription of pro-inflammatory markers that exacerbates renal I/R injury.
MATERIAL AND METHODS: . C57/6N and RIP3-/- mice as well as HK2 cells were used. Monolateral kidneys were subjected to 30 min of ischemia followed by either 12, 24, or 48 h of reperfusion. Protein levels of RIP3, Mitofilin, cGAS, STING, and p-p65 were measured using Western and immunofluorescence analysis, while IL-6, TNF-α, and ICAM-1 expressions as well as mtDNA release were assessed by qRT-PCR, ELISA. Kidney function was measured by blood urea nitrogen and creatinine kits, and the interaction between RIP3 and Mitofilin was measured by Co-Immunoprecipitation. In WT, RESULTS: . We found that renal I/R increased RIP3 levels, and its translocation into mitochondria. We observed that RIP3 interacts with Mitofilin likely promoting its degradation. While renal I/R associated with mitochondria damage, increased mtDNA release, activation of cGAS/STING/p65 pathway and increased transcription of pro-inflammatory markers including IL-6, TNF-α and ICAM-1, all these effects were decreased in RIP3-/- mice. In HK-2, RIP3 overexpression or Mitofilin knockdown increased cell death by activating the cGAS-STING/p65 pathway.
CONCLUSION: . We demonstrated that kidney I/R increases RIP3 levels in the cytosol and it translocates into mitochondria, where it interacts with and promote Mitofilin degradation leading to increased mitochondrial structures damage and dysfunction. The subsequent increase in ROS production in mitochondria is postulated to facilitate mtDNA damage and release into the cytosol where it activates the cGAS/STING/p-p65 pathway leading to amplified nuclear transcription of pro-inflammatory markers that subsequently increase renal I/R injury. Together, this study point to an important role of RIP3 in the initiation and development of renal I/R injury.

DOI: https://doi.org/10.1096/fasebj.2022.36.S1.R3839
FASEB J. 2022 May;36 Suppl 1

Targeting Hypoxia-Adenosinergic Signaling to Enable Effective Anti-Tumor Responses by Reprogramming the Immunosuppressive Tumor Microenvironment.

Kai Beattie, Nuria Roxana Romero Navarrete, Anushka Dongre, Michail Sitkovsky, Stephen Hatfield.

The hypoxia-HIF-1ɑ-mediated generation of extracellular adenosine (eADO) and associated A2A adenosine receptor (A2AR) signaling represent a critical mechanism for resistance to anti-tumor immune attack in an immunosuppressive tumor microenvironment (TME). This is supported by earlier clinical and preclinical findings that tumors exhibiting refractory responses to chemotherapeutic and immunotherapeutic interventions are often characterized by low tissue oxygen tension and elevation of intracellular cAMP triggered by the binding of adenosine to the A2AR. The ensuing signaling cascade results in the downregulation of T cell activation and increased production of anti-inflammatory factors. Several classes of drugs have been proven in preclinical studies and clinical trials to weaken this powerful biochemical mechanism of immunosuppression and enable tumor rejection. Therapeutic approaches targeting the upstream and downstream stages of hypoxia-adenosinergic negative immune regulation (i.e. A2AR antagonists, oxygenation, inhibition of adenosine generation or adenosine degradation) represent promising co-adjuvants capable of inducing a more immunopermissive TME. The removal of this biochemical barrier may be the key to unleashing the full therapeutic potential of immunotherapies. For instance, the epithelial-mesenchymal transition (EMT) program, which confers the ability of cancer cells to engage in metastatic dissemination, is associated with the acquisition of resistance to immune checkpoint blockade (ICB). Recent studies have demonstrated that abrogation of the adenosine-generating ectoenzyme CD73 sensitizes mice bearing quasi-mesenchymal (qM) tumors to anti-CTLA4 ICB through an increase in CD8+ T cell infiltration and cytotoxicity. Furthermore, the present study demonstrates the differential expression of adenosinergic enzymes and EMT transcription factors (EMT-TFs) in murine breast epithelial (E) and qM carcinoma cell lines cultured in normoxic (21% oxygen) and hypoxic (1% oxygen) conditions in vitro. As hypothesized, the stabilization of HIF-1ɑ in hypoxic conditions resulted in the upregulation of some adenosine-generating enzymes and changes in adenosine metabolism. These results elucidate an additional mechanism through which hypoxia can contribute to the assembly of an immunosuppressive TME, while highlighting the categorical differences between the E vs qM states of carcinoma cells.

DOI: https://doi.org/10.1096/fasebj.2022.36.S1.R3572
Int J Oncol. 2022 Jun;pii: 79. [Epub ahead of print]60(6):

TRAP1 regulates the response of colorectal cancer cells to hypoxia and inhibits ribosome biogenesis under conditions of oxygen deprivation.

Giuseppina Bruno, Valeria Li Bergolis, Annamaria Piscazzi, Fabiana Crispo, Valentina Condelli, Pietro Zoppoli, Francesca Maddalena, Michele Pietrafesa, Guido Giordano, Danilo Swann Matassa, Franca Esposito, Matteo Landriscina.

  Metabolic rewiring fuels rapid cancer cell proliferation by promoting adjustments in energetic resources, and increasing glucose uptake and its conversion into lactate, even in the presence of oxygen. Furthermore, solid tumors often contain hypoxic areas and can rapidly adapt to low oxygen conditions by activating hypoxia inducible factor (HIF)‑1α and several downstream pathways, thus sustaining cell survival and metabolic reprogramming. Since TNF receptor‑associated protein 1 (TRAP1) is a HSP90 molecular chaperone upregulated in several human malignancies and is involved in cancer cell adaptation to unfavorable environments and metabolic reprogramming, in the present study, its role was investigated in the adaptive response to hypoxia in human colorectal cancer (CRC) cells and organoids. In the present study, glucose uptake, lactate production and the expression of key metabolic genes were evaluated in TRAP1‑silenced CRC cell models under conditions of hypoxia/normoxia. Whole genome gene expression profiling was performed in TRAP1‑silenced HCT116 cells exposed to hypoxia to establish the role of TRAP1 in adaptive responses to oxygen deprivation. The results revealed that TRAP1 was involved in regulating hypoxia‑induced HIF‑1α stabilization and glycolytic metabolism and that glucose transporter 1 expression, glucose uptake and lactate production were partially impaired in TRAP1‑silenced CRC cells under hypoxic conditions. At the transcriptional level, the gene expression reprogramming of cancer cells driven by HIF‑1α was partially inhibited in TRAP1‑silenced CRC cells and organoids exposed to hypoxia. Moreover, Gene Set Enrichment Analysis of TRAP1‑silenced HCT116 cells exposed to hypoxia demonstrated that TRAP1 was involved in the regulation of ribosome biogenesis and this occurred with the inhibition of the mTOR pathway. Therefore, as demonstrated herein, TRAP1 is a key factor in maintaining HIF‑1α‑induced genetic/metabolic program under hypoxic conditions and may represent a promising target for novel metabolic therapies.

Keywords:  TNF receptor‑associated protein 1; glycolysis; hypoxia; hypoxia inducible factor 1α; ribosome biosynthesis

DOI:  https://doi.org/10.3892/ijo.2022.5369
Biomark Res. 2022 May 08. 10(1): 29

Sestrin2 in cancer: a foe or a friend?

Moein Ala.

  Sestrin2 is a conserved antioxidant, metabolism regulator, and downstream of P53. Sestrin2 can suppress oxidative stress and inflammation, thereby preventing the development and progression of cancer. However, Sestrin2 attenuates severe oxidative stress by activating nuclear factor erythroid 2-related factor 2 (Nrf2), thereby enhancing cancer cells survival and chemoresistance. Sestrin2 inhibits endoplasmic reticulum stress and activates autophagy and apoptosis in cancer cells. Attenuation of endoplasmic reticulum stress and augmentation of autophagy hinders cancer development but can either expedite or impede cancer progression under specific conditions. Furthermore, Sestrin2 can vigorously inhibit oncogenic signaling pathways through downregulation of mammalian target of rapamycin complex 1 (mTORC1) and hypoxia-inducible factor 1-alpha (HIF-1α). Conversely, Sestrin2 decreases the cytotoxic activity of T cells and natural killer cells which helps tumor cells immune evasion. Sestrin2 can enhance tumor cells viability in stress conditions such as glucose or glutamine deficiency. Cancer cells can also upregulate Sestrin2 during chemotherapy or radiotherapy to attenuate severe oxidative stress and ER stress, augment autophagy and resist the treatment. Recent studies unveiled that Sestrin2 is involved in the development and progression of several types of human cancer. The effect of Sestrin2 may differ depending on the type of tumor, for instance, several studies revealed that Sestrin2 protects against colorectal cancer, whereas results are controversial regarding lung cancer. Furthermore, Sestrin2 expression correlates with metastasis and survival in several types of human cancer such as colorectal cancer, lung cancer, and hepatocellular carcinoma. Targeted therapy for Sestrin2 or regulation of its expression by new techniques such as non-coding RNAs delivery and vector systems may improve cancer chemotherapy and overcome chemoresistance, metastasis and immune evasion that should be investigated by future trials.

Keywords:  Apoptosis; Autophagy; Cancer; Oxidative stress; Sestrin2; mTORC1

DOI:  https://doi.org/10.1186/s40364-022-00380-6