Acid-base transport in pancreatic cancer: Molecular mechanisms and clinical potential

2014 ◽  
Vol 92 (6) ◽  
pp. 449-459 ◽  
Author(s):  
Su Chii Kong ◽  
Andrea Gianuzzo ◽  
Ivana Novak ◽  
Stine Falsig Pedersen
Keyword(s):  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Ph Regulation ◽  
Treatment Options ◽  
Ductal Adenocarcinoma ◽  
Cancer Type ◽  
Ph Homeostasis ◽  
Acid Base ◽  
Acid Extrusion ◽  
Transporter Expression

Solid tumors are characterized by a microenvironment that is highly acidic, while intracellular pH (pHi) is normal or even elevated. This is the result of elevated metabolic rates in the highly proliferative cancer cells, in conjunction with often greatly increased rates of net cellular acid extrusion. Studies in various cancers have suggested that while the acid extrusion mechanisms employed are generally the same as those in healthy cells, the specific transporters upregulated vary with the cancer type. The main such transporters include Na+/H+ exchangers, various HCO3− transporters, H+ pumps, and lactate-H+ cotransporters. The mechanisms leading to their dysregulation in cancer are incompletely understood but include changes in transporter expression levels, trafficking and membrane localization, and posttranslational modifications. In turn, accumulating evidence has revealed that in addition to supporting their elevated metabolic rate, their increased acid efflux capacity endows the cancer cells with increased capacity for invasiveness, proliferation, and chemotherapy resistance. The pancreatic duct exhibits an enormous capacity for acid-base transport, rendering pHi dysregulation a potentially very important topic in pancreatic ductal adenocarcinoma (PDAC). PDAC — accounting for about 90% of all pancreatic cancers — has one of the highest cancer mortality rates known, and new diagnostic and treatment options are highly needed. However, very little is known about whether pH regulation is altered in PDAC and, if so, the possible role of this in cancer development. Here, we review current models for pancreatic acid-base transport and pH homeostasis and summarize current views on acid-base dysregulation in cancer, focusing where possible on the few studies to date in PDAC. Finally, we present new data-mining analyses of acid-base transporter expression changes in PDAC and discuss essential directions for future work.

scholarly journals Inhibition of mutant KRAS-driven overexpression of ARF6 and MYC by an eIF4A inhibitor drug improves the effects of anti-PD-1 immunotherapy for pancreatic cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ari Hashimoto ◽  
Haruka Handa ◽  
Soichiro Hata ◽  
Akio Tsutaho ◽  
Takao Yoshida ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Mrna Translation ◽  
Immune Checkpoint Blockade ◽  
Small Gtpase ◽  
Initiation Factor ◽  
Ductal Adenocarcinoma ◽  
Cancer Type ◽  
Intact Cells ◽  
Cell Functions

AbstractMany clinical trials are being conducted to clarify effective combinations of various drugs for immune checkpoint blockade (ICB) therapy. However, although extensive studies from multiple aspects have been conducted regarding treatments for pancreatic ductal adenocarcinoma (PDAC), there are still no effective ICB-based therapies or biomarkers for this cancer type. A series of our studies have identified that the small GTPase ARF6 and its downstream effector AMAP1 (also called ASAP1/DDEF1) are often overexpressed in different cancers, including PDAC, and closely correlate with poor patient survival. Mechanistically, the ARF6-AMAP1 pathway drives cancer cell invasion and immune evasion, via upregulating β1-integrins and PD-L1, and downregulating E-cadherin, upon ARF6 activation by external ligands. Moreover, the ARF6-AMAP1 pathway enhances the fibrosis caused by PDAC, which is another barrier for ICB therapies. KRAS mutations are prevalent in PDACs. We have shown previously that oncogenic KRAS mutations are the major cause of the aberrant overexpression of ARF6 and AMAP1, in which KRAS signaling enhances eukaryotic initiation factor 4A (eIF4A)-dependent ARF6 mRNA translation and eIF4E-dependent AMAP1 mRNA translation. MYC overexpression is also a key pathway in driving cancer malignancy. MYC mRNA is also known to be under the control of eIF4A, and the eIF4A inhibitor silvestrol suppresses MYC and ARF6 expression. Using a KPC mouse model of human PDAC (LSL-Kras(G12D/+); LSL-Trp53(R172H/+)); Pdx-1-Cre), we here demonstrate that inhibition of the ARF6-AMAP1 pathway by shRNAs in cancer cells results in therapeutic synergy with an anti-PD-1 antibody in vivo; and furthermore, that silvestrol improves the efficacy of anti-PD-1 therapy, whereas silvestrol on its own promotes tumor growth in vivo. ARF6 and MYC are both essential for normal cell functions. We demonstrate that silvestrol substantially mitigates the overexpression of ARF6 and MYC in KRAS-mutated cells, whereas the suppression is moderate in KRAS-intact cells. We propose that targeting eIF4A, as well as mutant KRAS, provides novel methods to improve the efficacy of anti-PD-1 and associated ICB therapies against PDACs, in which ARF6 and AMAP1 overexpression, as well as KRAS mutations of cancer cells are biomarkers to identify patients with drug-susceptible disease. The same may be applicable to other cancers with KRAS mutations.

scholarly journals Extracellular Acid-Base Balance and Ion Transport Between Body Fluid Compartments

Physiology ◽  
2017 ◽  
Vol 32 (5) ◽  
pp. 367-379 ◽  
Author(s):  
Julian L. Seifter ◽  
Hsin-Yun Chang
Keyword(s):  
Ion Transport ◽  
Ph Regulation ◽  
Extracellular Fluid ◽  
Transport Processes ◽  
Electrolyte Balance ◽  
Ph Homeostasis ◽  
Acid Base Balance ◽  
Acid Base ◽  
Base Balance ◽  
Fluid Compartments

Clinical assessment of acid-base disorders depends on measurements made in the blood, part of the extracellular compartment. Yet much of the metabolic importance of these disorders concerns intracellular events. Intracellular and interstitial compartment acid-base balance is complex and heterogeneous. This review considers the determinants of the extracellular fluid pH related to the ion transport processes at the interface of cells and the interstitial fluid, and between epithelial cells lining the transcellular contents of the gastrointestinal and urinary tracts that open to the external environment. The generation of acid-base disorders and the associated disruption of electrolyte balance are considered in the context of these membrane transporters. This review suggests a process of internal and external balance for pH regulation, similar to that of potassium. The role of secretory gastrointestinal epithelia and renal epithelia with respect to normal pH homeostasis and clinical disorders are considered. Electroneutrality of electrolytes in the ECF is discussed in the context of reciprocal changes in Cl−or non Cl−anions and [Formula: see text].

scholarly journals Metabolic plasticity imparts erlotinib-resistance in pancreatic cancer by upregulating glucose-6-phosphate dehydrogenase

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Neha Sharma ◽  
Alok Bhushan ◽  
Jun He ◽  
Gagan Kaushal ◽  
Vikas Bhardwaj
Keyword(s):  
Pancreatic Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Treatment Options ◽  
Pentose Phosphate ◽  
Metabolic Phenotype ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Resistant Cells

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant forms of cancer. Lack of effective treatment options and drug resistance contributes to the low survival among PDAC patients. In this study, we investigated the metabolic alterations in pancreatic cancer cells that do not respond to the EGFR inhibitor erlotinib. We selected erlotinib-resistant pancreatic cancer cells from MiaPaCa2 and AsPC1 cell lines. Metabolic profiling of erlotinib-resistant cells revealed a significant downregulation of glycolytic activity and reduced level of glycolytic metabolites compared to the sensitive cells. The resistant cells displayed elevated expression of the pentose phosphate pathway (PPP) enzymes involved in ROS regulation and nucleotide biosynthesis. The enhanced PPP elevated cellular NADPH/NADP+ ratio and protected the cells from reactive oxygen species (ROS)-induced damage. Inhibition of PPP using 6-aminonicotinamide (6AN) elevated ROS levels, induced G1 cell cycle arrest, and sensitized resistant cells to erlotinib. Genetic studies identified elevated PPP enzyme glucose-6-phosphate dehydrogenase (G6PD) as an important contributor to erlotinib resistance. Mechanistically, our data showed that upregulation of inhibitor of differentiation (ID1) regulates G6PD expression in resistant cells thus contributing to altered metabolic phenotype and reduced response to erlotinib. Together, our results highlight an underlying role of tumor metabolism in PDAC drug response and identify G6PD as a target to overcome drug resistance.

Chronic continuous hypoxia decreases the expression of SLC4A7 (NBCn1) and SLC4A10 (NCBE) in mouse brain

2007 ◽  
Vol 293 (6) ◽  
pp. R2412-R2420 ◽  
Author(s):  
Li-Ming Chen ◽  
Inyeong Choi ◽  
Gabriel G. Haddad ◽  
Walter F. Boron
Keyword(s):  
Mouse Brain ◽  
Chronic Hypoxia ◽  
Ph Regulation ◽  
Protein Abundance ◽  
Ph Homeostasis ◽  
Acid Base ◽  
Protein Levels ◽  
Stage Of Development ◽  
Wide Range ◽  
The Central Nervous System

In the mammalian CNS, hypoxia causes a wide range of physiological effects, and these effects often depend on the stage of development. Among the effects are alterations in pH homeostasis. Na+-coupled HCO3− transporters can play critical roles in intracellular pH regulation and several, such as NCBE and NBCn1, are expressed abundantly in the central nervous system. In the present study, we examined the effect of chronic continuous hypoxia on the expression of two electroneutral Na-coupled HCO3− transporters, SLC4a7 (NBCn1) and SLC4a10 (NCBE), in mouse brain, the first such study on any acid-base transporter. We placed the mice in normobaric chambers and either maintained normoxia (21% inspired O2) or imposed continuous chronic hypoxia (11% O2) for a duration of either 14 days or 28 days, starting from ages of either postnatal age 2 days (P2) or P90. We assessed protein abundance by Western blot analysis, loading equal amounts of total protein for each condition. In most cases, hypoxia reduced NBCn1 levels by 20–50%, and NCBE levels by 15–40% in cerebral cortex, subcortex, cerebellum, and hippocampus, both after 14 and 28 days, and in both pups and adults. We hypothesize that these decreases, which are out of proportion to the expected overall decreases in brain protein levels, may especially be important for reducing energy consumption.

scholarly journals Transport Metabolons and Acid/Base Balance in Tumor Cells

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 899 ◽  
Author(s):  
Holger M. Becker ◽  
Joachim W. Deitmer
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Drug Targets ◽  
Ph Regulation ◽  
Host Cells ◽  
Bicarbonate Transport ◽  
Carbonic Anhydrases ◽  
Acid Base Balance ◽  
Acid Base ◽  
Base Balance

Solid tumors are metabolically highly active tissues, which produce large amounts of acid. The acid/base balance in tumor cells is regulated by the concerted interplay between a variety of membrane transporters and carbonic anhydrases (CAs), which cooperate to produce an alkaline intracellular, and an acidic extracellular, environment, in which cancer cells can outcompete their adjacent host cells. Many acid/base transporters form a structural and functional complex with CAs, coined “transport metabolon”. Transport metabolons with bicarbonate transporters require the binding of CA to the transporter and CA enzymatic activity. In cancer cells, these bicarbonate transport metabolons have been attributed a role in pH regulation and cell migration. Another type of transport metabolon is formed between CAs and monocarboxylate transporters, which mediate proton-coupled lactate transport across the cell membrane. In this complex, CAs function as “proton antenna” for the transporter, which mediate the rapid exchange of protons between the transporter and the surroundings. These transport metabolons do not require CA catalytic activity, and support the rapid efflux of lactate and protons from hypoxic cancer cells to allow sustained glycolytic activity and cell proliferation. Due to their prominent role in tumor acid/base regulation and metabolism, transport metabolons might be promising drug targets for new approaches in cancer therapy.

scholarly journals Unfolded Protein Response (UPR) in Survival, Dormancy, Immunosuppression, Metastasis, and Treatments of Cancer Cells

2019 ◽  
Vol 20 (10) ◽  
pp. 2518 ◽  
Author(s):  
Sheng-Kai Hsu ◽  
Chien-Chih Chiu ◽  
Hans-Uwe Dahms ◽  
Chon-Kit Chou ◽  
Chih-Mei Cheng ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Cancer Cells ◽  
Protein Modification ◽  
Molecular Mechanisms ◽  
Heart Diseases ◽  
Treatment Options ◽  
Misfolded Proteins ◽  
Cancer Proliferation ◽  
Unfolded Protein ◽  
Protein Response

The endoplasmic reticulum (ER) has diverse functions, and especially misfolded protein modification is in the focus of this review paper. With a highly regulatory mechanism, called unfolded protein response (UPR), it protects cells from the accumulation of misfolded proteins. Nevertheless, not only does UPR modify improper proteins, but it also degrades proteins that are unable to recover. Three pathways of UPR, namely PERK, IRE-1, and ATF6, have a significant role in regulating stress-induced physiological responses in cells. The dysregulated UPR may be involved in diseases, such as atherosclerosis, heart diseases, amyotrophic lateral sclerosis (ALS), and cancer. Here, we discuss the relation between UPR and cancer, considering several aspects including survival, dormancy, immunosuppression, angiogenesis, and metastasis of cancer cells. Although several moderate adversities can subject cancer cells to a hostile environment, UPR can ensure their survival. Excessive unfavorable conditions, such as overloading with misfolded proteins and nutrient deprivation, tend to trigger cancer cell death signaling. Regarding dormancy and immunosuppression, cancer cells can survive chemotherapies and acquire drug resistance through dormancy and immunosuppression. Cancer cells can also regulate the downstream of UPR to modulate angiogenesis and promote metastasis. In the end, regulating UPR through different molecular mechanisms may provide promising anticancer treatment options by suppressing cancer proliferation and progression.

Hedgehog Promotes Neovascularization through the Regulation of Bone-Marrow Derived Progenitors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3048-3048
Author(s):  
Yusuke Mizukami ◽  
Junpei Sasajima ◽  
Kazumasa Nakamura ◽  
Kazuya Sato ◽  
Yoshiaki Sugiyama ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Tumor Vasculature ◽  
Ductal Adenocarcinoma ◽  
Mrna Levels ◽  
Development Organization ◽  
Hh Signaling

Abstract Abstract 3048 Poster Board II-1024 The hedgehog (Hh) pathway has been implicated in the development of embryonic blood vessels and pathogenesis of cancer. Smoothened (Smo), one of the receptors in Hh signaling, is a promising molecular target for the treatment of malignancies. Pancreatic ductal adenocarcinoma (PDAC) is one of the tumors in which sonic hedgehog (Shh) is misexpressed. Although there are cell-autonomous effects of Hh on the proliferation of tumor cells, recent studies have demonstrated an oncogenic function of Hh in stromal cells. Cyclopamine antagonizes Smo and can attenuate PDAC growth in mice, resulting in regression of the tumor vasculature with reduced pericyte coverage. However, the inhibitory effect of cyclopamine on proliferation of KP-1N cells, a human PDAC line highly expressing Shh, was modest, indicating additional effects of Hh signaling on tumor progression. Here, we have identified novel molecular mechanisms by which Hh regulates tumor angiogenesis. Expression of Gli2 protein in the stroma, but not in cancer cells, was attenuated markedly by cyclopamine administration, consistent with the general absence of autocrine Hh signaling in PDAC cells. Cyclopamine significantly attenuated the homing of bone marrow (BM)-derived cells into KP-1N xenografts and their interaction with the tumor vasculature, suggesting that Hh signaling may play a role during migration and differentiation of BM-derived progenitors to participate in neovascularization. Host derived Ang-1 and IGF-1 mRNA levels in xenografts were strongly downregulated by cyclopamine, which may contribute to the maintenance and maturation of tumor vasculature. In vitro co-culture experiments demonstrated that KP-1N cells induced Ang-1/IGF-1 production in BM-progenitors (c-Kit+ fraction of BM mononuclear cell), and this induction was significantly attenuated either by cyclopamine or lentiviral shRNA targeting Smo. In addition, in vitro tube formation assay with the mouse endothelial line MS-1 and a matrigel plug assay supports the role of Shh secreted from PDAC cells to induce migration and capillary formation of BM-derived progenitors. IGF-1 is a crucial target of Hh signaling in BM-derived cells during neovascularization, since anti-IGF-1 neutralizing antibody blocked the induction of the capillary morphogenesis by BM-progenitors. Finally, this “paracrine” effect of Hh seems to be a late event during pancreatic tumorigenesis, as stromal Patch1/Gli2 expression was detected within PDAC lesions in Pdx1-Cre;LSL-KrasG12D;p53lox/+ mice, but not in PanIN lesion, a potential precursor of PDAC, in Pdx1-Cre;LSL-KrasG12D mice. We also observed upregulation of VE-cadherin and Ptch1 mRNA in lineage–/c-Kit+ fraction of BM mononuclear cells (primitive BM-derived progenitors) from PDAC mice as compared to wild-type/PanIN mice, suggesting that pro-angiogenic conditions are prepared at the level of the BM in cancer-bearing hosts. The primitive progenitors derived from ‘activated BM’ are imported to the tumor microenvironment where they become fully activated. Hh-ligand from cancer cells can therefore have a profound effect on neovascularization through the regulation of the progenitors during late stages of tumorigenesis. This work was supported by New Energy and Industrial Technology Development Organization (NEDO) of Japan. Disclosures No relevant conflicts of interest to declare.

Molecular profile of breast versus ovarian cancer cells in response to treatment with the anticancer drugs cisplatin, carboplatin, doxorubicin, etoposide and taxol

2008 ◽  
Vol 389 (11) ◽  
Author(s):  
Hellinida Thomadaki ◽  
Andreas Scorilas
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Molecular Mechanisms ◽  
Mrna Level ◽  
Response To Treatment ◽  
Molecular Profile ◽  
Ovarian Cancer Cells ◽  
Chemotherapy Response ◽  
Cancer Type

Abstract We assessed changes in the apoptosis-related genes BCL2, BAX, BCL2L12, FAS and CASPASE-3 in OVCAR-3 human ovarian cancer cells and BT-20 human breast cancer cells to provide an insight into the molecular mechanisms involved in the response of these cells to treatment with anticancer drugs and to assess their value as potential biomarkers of chemotherapy response in breast and ovarian cancer. Cells were treated with different chemotherapeutic drugs (cisplatin, carboplatin, doxorubicin, etoposide and taxol) and assessed for changes in the expression of apoptosis-related genes at the mRNA level. Total RNA was extracted, reverse-transcribed into cDNA and amplified by PCR using gene-specific primers. GAPDH was used as a housekeeping gene. Cytotoxicity was assessed by MTT assay. Both cancer cell lines responded differentially at the molecular level to the drug treatments. OVCAR-3 cells showed more pronounced sensitivity and changes compared to BT-20 cells at the mRNA level for different apoptosis-related genes, leading to cell and cancer type dependence in conjunction with drug dependence.

scholarly journals Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yu Wang ◽  
Yiyi Liang ◽  
Haiyan Xu ◽  
Xiao Zhang ◽  
Tiebo Mao ◽  
...  
Keyword(s):  
Single Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Immune Cells ◽  
Poor Prognosis ◽  
Single Cell Analysis ◽  
Treatment Options ◽  
Objective Response ◽  
Complete Response ◽  
Ductal Adenocarcinoma

AbstractThe current pathological and molecular classification of pancreatic ductal adenocarcinoma (PDAC) provides limited guidance for treatment options, especially for immunotherapy. Cancer-associated fibroblasts (CAFs) are major players of desmoplastic stroma in PDAC, modulating tumor progression and therapeutic response. Using single-cell RNA sequencing, we explored the intertumoral heterogeneity among PDAC patients with different degrees of desmoplasia. We found substantial intertumoral heterogeneity in CAFs, ductal cancer cells, and immune cells between the extremely dense and loose types of PDACs (dense-type, high desmoplasia; loose-type, low desmoplasia). Notably, no difference in CAF abundance was detected, but a novel subtype of CAFs with a highly activated metabolic state (meCAFs) was found in loose-type PDAC compared to dense-type PDAC. MeCAFs had highly active glycolysis, whereas the corresponding cancer cells used oxidative phosphorylation as a major metabolic mode rather than glycolysis. We found that the proportion and activity of immune cells were much higher in loose-type PDAC than in dense-type PDAC. Then, the clinical significance of the CAF subtypes was further validated in our PDAC cohort and a public database. PDAC patients with abundant meCAFs had a higher risk of metastasis and a poor prognosis but showed a dramatically better response to immunotherapy (64.71% objective response rate, one complete response). We characterized the intertumoral heterogeneity of cellular components, immune activity, and metabolic status between dense- and loose-type PDACs and identified meCAFs as a novel CAF subtype critical for PDAC progression and the susceptibility to immunotherapy.

scholarly journals Loss of p53 tumor suppression function drives invasion and genomic instability in models of murine pancreatic cancer

2022 ◽  
Author(s):  
Claudia Tonelli ◽  
Astrid Deschênes ◽  
Melissa A. Yao ◽  
Youngkyu Park ◽  
David A. Tuveson
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Morphological Changes ◽  
Treatment Options ◽  
Intraepithelial Neoplasia ◽  
Ductal Adenocarcinoma ◽  
Wild Type

Pancreatic ductal adenocarcinoma (PDA) is a deadly disease with few treatment options. There is an urgent need to better understand the molecular mechanisms that drive disease progression, with the ultimate aim of identifying early detection markers and clinically actionable targets. To investigate the transcriptional and morphological changes associated with pancreatic cancer progression, we analyzed the KrasLSLG12D/+; Trp53LSLR172H/+; Pdx1-Cre (KPC) mouse model. We have identified an intermediate cellular event during pancreatic carcinogenesis in the KPC mouse model of PDA that is represented by a subpopulation of tumor cells that express KrasG12D, p53R172H and one allele of wild-type Trp53. In vivo, these cells represent a histological spectrum of pancreatic intraepithelial neoplasia (PanIN) and acinar-to-ductal metaplasia (ADM) and rarely proliferate. Following loss of wild-type p53, these precursor lesions undergo malignant de-differentiation and acquire invasive features. We have established matched organoid cultures of pre-invasive and invasive cells from murine PDA. Expression profiling of the organoids led to the identification of markers of the pre-invasive cancer cells in vivo and mechanisms of disease aggressiveness.

Sign in / Sign up

Export Citation Format

Share Document