-
1.
Isoforms of autophagy-related proteins: role in glioma progression and therapy resistance.
Belyaeva, E, Kharwar, RK, Ulasov, IV, Karlina, I, Timashev, P, Mohammadinejad, R, Acharya, A
Molecular and cellular biochemistry. 2022;(2):593-604
Abstract
Autophagy is the process of recycling and utilization of degraded organelles and macromolecules in the cell compartments formed during the fusion of autophagosomes with lysosomes. During autophagy induction the healthy and tumor cells adapt themselves to harsh conditions such as cellular stress or insufficient supply of nutrients in the cell environment to maintain their homeostasis. Autophagy is currently seen as a form of programmed cell death along with apoptosis and necroptosis. In recent years multiple studies have considered the autophagy as a potential mechanism of anticancer therapy in malignant glioma. Although, subsequent steps in autophagy development are known and well-described, on molecular level the mechanism of autophagosome initiation and maturation using autophagy-related proteins is under investigation. This article reviews current state about the mechanism of autophagy, its molecular pathways and the most recent studies on roles of autophagy-related proteins and their isoforms in glioma progression and its treatment.
-
2.
PSMA PET/CT guided intensification of therapy in patients at risk of advanced prostate cancer (PATRON): a pragmatic phase III randomized controlled trial.
Ménard, C, Young, S, Zukotynski, K, Hamilton, RJ, Bénard, F, Yip, S, McCabe, C, Saad, F, Brundage, M, Nitulescu, R, et al
BMC cancer. 2022;(1):251
Abstract
BACKGROUND Positron emission tomography targeting the prostate specific membrane antigen (PSMA PET/CT) has demonstrated unparalleled performance as a staging examination for prostate cancer resulting in substantial changes in management. However, the impact of altered management on patient outcomes is largely unknown. This study aims to assess the impact of intensified radiotherapy or surgery guided by PSMA PET/CT in patients at risk of advanced prostate cancer. METHODS This pan-Canadian phase III randomized controlled trial will enroll 776 men with either untreated high risk prostate cancer (CAPRA score 6-10 or stage cN1) or biochemically recurrent prostate cancer post radical prostatectomy (PSA > 0.1 ng/mL). Patients will be randomized 1:1 to either receive conventional imaging or conventional plus PSMA PET imaging, with intensification of radiotherapy or surgery to newly identified disease sites. The primary endpoint is failure free survival at 5 years. Secondary endpoints include rates of adverse events, time to next-line therapy, as well as impact on health-related quality of life and cost effectiveness as measured by incremental cost per Quality Adjusted Life Years gained. DISCUSSION This study will help create level 1 evidence needed to demonstrate whether or not intensification of radiotherapy or surgery based on PSMA PET findings improves outcomes of patients at risk of advanced prostate cancer in a manner that is cost-effective. TRIAL REGISTRATION This trial was prospectively registered in ClinicalTrials.gov as NCT04557501 on September 21, 2020.
-
3.
CHFR regulates chemoresistance in triple-negative breast cancer through destabilizing ZEB1.
Luo, H, Zhou, Z, Huang, S, Ma, M, Zhao, M, Tang, L, Quan, Y, Zeng, Y, Su, L, Kim, J, et al
Cell death & disease. 2021;(9):820
Abstract
Failures to treat triple-negative breast cancer (TNBC) are mainly due to chemoresistance or radioresistance. We and others previously discovered that zinc finger E-box-binding homeobox 1 (ZEB1) is a massive driver causing these resistance. However, how to dynamically modulate the intrinsic expression of ZEB1 during cell cycle progression is elusive. Here integrated affinity purification combined with mass spectrometry and TCGA analysis identify a cell cycle-related E3 ubiquitin ligase, checkpoint with forkhead and ring finger domains (CHFR), as a key negative regulator of ZEB1 in TNBC. Functional studies reveal that CHFR associates with and decreases ZEB1 expression in a ubiquitinating-dependent manner and that CHFR represses fatty acid synthase (FASN) expression through ZEB1, leading to significant cell death of TNBC under chemotherapy. Intriguingly, a small-molecule inhibitor of HDAC under clinical trial, Trichostatin A (TSA), increases the expression of CHFR independent of histone acetylation, thereby destabilizes ZEB1 and sensitizes the resistant TNBC cells to conventional chemotherapy. In patients with basal-like breast cancers, CHFR levels significantly correlates with survival. These findings suggest the therapeutic potential for targeting CHFR-ZEB1 signaling in resistant malignant breast cancers.
-
4.
Defects in the STIM1 SOARα2 domain affect multiple steps in the CRAC channel activation cascade.
Höglinger, C, Grabmayr, H, Maltan, L, Horvath, F, Krobath, H, Muik, M, Tiffner, A, Renger, T, Romanin, C, Fahrner, M, et al
Cellular and molecular life sciences : CMLS. 2021;(19-20):6645-6667
-
-
Free full text
-
Abstract
The calcium release-activated calcium (CRAC) channel consists of STIM1, a Ca2+ sensor in the endoplasmic reticulum (ER), and Orai1, the Ca2+ ion channel in the plasma membrane. Ca2+ store depletion triggers conformational changes and oligomerization of STIM1 proteins and their direct interaction with Orai1. Structural alterations include the transition of STIM1 C-terminus from a folded to an extended conformation thereby exposing CAD (CRAC activation domain)/SOAR (STIM1-Orai1 activation region) for coupling to Orai1. In this study, we discovered that different point mutations of F394 in the small alpha helical segment (STIM1 α2) within the CAD/SOAR apex entail a rich plethora of effects on diverse STIM1 activation steps. An alanine substitution (STIM1 F394A) destabilized the STIM1 quiescent state, as evident from its constitutive activity. Single point mutation to hydrophilic, charged amino acids (STIM1 F394D, STIM1 F394K) impaired STIM1 homomerization and subsequent Orai1 activation. MD simulations suggest that their loss of homomerization may arise from altered formation of the CC1α1-SOAR/CAD interface and potential electrostatic interactions with lipid headgroups in the ER membrane. Consistent with these findings, we provide experimental evidence that the perturbing effects of F394D depend on the distance of the apex from the ER membrane. Taken together, our results suggest that the CAD/SOAR apex is in the immediate vicinity of the ER membrane in the STIM1 quiescent state and that different mutations therein can impact the STIM1/Orai1 activation cascade in various manners. Legend: Upon intracellular Ca2+ store depletion of the endoplasmic reticulum (ER), Ca2+ dissociates from STIM1. As a result, STIM1 adopts an elongated conformation and elicits Ca2+ influx from the extracellular matrix (EM) into the cell due to binding to and activation of Ca2+-selective Orai1 channels (left). The effects of three point mutations within the SOARα2 domain highlight the manifold roles of this region in the STIM1/Orai1 activation cascade: STIM1 F394A is active irrespective of the intracellular ER Ca2+ store level, but activates Orai1 channels to a reduced extent (middle). On the other hand, STIM1 F394D/K cannot adopt an elongated conformation upon Ca2+ store-depletion due to altered formation of the CC1α1-SOAR/CAD interface and/or electrostatic interaction of the respective side-chain charge with corresponding opposite charges on lipid headgroups in the ER membrane (right).
-
5.
Cumulative risks of colorectal cancer in Han Chinese patients with Lynch syndrome in Taiwan.
Kamiza, AB, Wang, WC, You, JF, Tang, R, Chien, HT, Lai, CH, Chiu, LL, Lo, TP, Hung, KY, Hsiung, CA, et al
Scientific reports. 2021;(1):8899
Abstract
Patients with Lynch syndrome have a high risk of colorectal cancer (CRC). In this study, we estimated the age- and sex-specific cumulative risks of CRC in Han Chinese patients with Lynch syndrome caused by the pathogenic germline mutations in MLH1 or MSH2 in Taiwan. Based on 321 mutation carriers and 419 non-mutation carriers from 75 pedigrees collected in an Amsterdam criteria family registry in Taiwan, the age- and sex-specific cumulative risks of CRC in male carriers of mutation in MLH1 and MSH2 at the age of 70 years were 60.3% (95% confidence interval (CI) = 31.1%-89.9%) and 76.7% (95% CI = 37.2%-99.0%), respectively. For females, the cumulative risks of CRC at the age of 70 were estimated to be 30.6% (95% CI = 14.3%-57.7%) and 49.3% (95% CI = 21.9%-84.5%) in the carriers of MLH1 and MSH2 germline mutations, respectively. In conclusion, the cumulative risks of CRC at the age of 70 in the Han Chinese patients is higher in mutation carriers than non-mutation carriers and male mutation carriers have a higher cumulative risk of developing CRC than the female mutation carriers.
-
6.
Nicotinamide N-Methyltransferase in Acquisition of Stem Cell Properties and Therapy Resistance in Cancer.
Novak Kujundžić, R, Prpić, M, Đaković, N, Dabelić, N, Tomljanović, M, Mojzeš, A, Fröbe, A, Trošelj, KG
International journal of molecular sciences. 2021;(11)
Abstract
The activity of nicotinamide N-methyltransferase (NNMT) is tightly linked to the maintenance of the nicotinamide adenine dinucleotide (NAD+) level. This enzyme catalyzes methylation of nicotinamide (NAM) into methyl nicotinamide (MNAM), which is either excreted or further metabolized to N1-methyl-2-pyridone-5-carboxamide (2-PY) and H2O2. Enzymatic activity of NNMT is important for the prevention of NAM-mediated inhibition of NAD+-consuming enzymes poly-adenosine -diphosphate (ADP), ribose polymerases (PARPs), and sirtuins (SIRTs). Inappropriately high expression and activity of NNMT, commonly present in various types of cancer, has the potential to disrupt NAD+ homeostasis and cellular methylation potential. Largely overlooked, in the context of cancer, is the inhibitory effect of 2-PY on PARP-1 activity, which abrogates NNMT's positive effect on cellular NAD+ flux by stalling liberation of NAM and reducing NAD+ synthesis in the salvage pathway. This review describes, and discusses, the mechanisms by which NNMT promotes NAD+ depletion and epigenetic reprogramming, leading to the development of metabolic plasticity, evasion of a major tumor suppressive process of cellular senescence, and acquisition of stem cell properties. All these phenomena are related to therapy resistance and worse clinical outcomes.
-
7.
New promising developments for potential therapeutic applications of high-dose ascorbate as an anticancer drug.
Testa, U, Pelosi, E, Castelli, G
Hematology/oncology and stem cell therapy. 2021;(3):179-191
Abstract
Vitamin C (ascorbate) is an essential dietary requirement, with fundamental redox, anti-oxidant functions at physiologic concentrations. Vitamin C is a cofactor for Fe2+ and 2-oxoglutarate-dependent dioxygenases, englobing large families of enzymes, including also epigenetic regulators of DNA and histone methylation. Importantly, vitamin C is involved in the control of the activity of TET (ten-eleven translocation) enzymes, key epigenetic regulators. For this spectrum of activities, often involving pathways deregulated in cancer cells, vitamin C possesses some pharmacologic activities that can be exploited in anticancer therapy. In particular, the capacity of pharmacological doses of vitamin C to target redox imbalance and to rescue deregulated epigenetic program observed in some cancer cells represents a consistent therapeutic potentiality. Several recent studies have identified some cancer subsets that could benefit from the pharmacological activities of vitamin C. The identification of these potentially responsive patients will help to carefully define controlled clinical trials aiming to evaluate the anticancer activity of Vitamin C.
-
8.
Na/K-ATPase: Their role in cell adhesion and migration in cancer.
Silva, CID, Gonçalves-de-Albuquerque, CF, Moraes, BPT, Garcia, DG, Burth, P
Biochimie. 2021;:1-8
Abstract
Na/K-ATPase (NKA) is a p-type transmembrane enzyme formed by three different subunits (α, β, and γ gamma). Primarily responsible for transporting sodium and potassium through the cell membrane, it also plays a critical role in intracellular signaling. The activation of diverse intracellular pathways may trigger cell death, survival, or even cell proliferation. Changes in the NKA functions or expression in isoforms subunits impact pathological conditions, such as cancer. The NKA function affects cell adhesion, motility, and migration, which are different in the physiological and pathological states. All enzyme subunits take part in the cell adhesion process, with the β subunit being the most studied. Thus, herein we aim to highlight NKA' central role in cell adhesion, motility, and migration in cancer cells.
-
9.
Association of C677T (rs1081133) and A1298C (rs1801131) Methylenetetrahydrofolate Reductase Variants with Breast Cancer Susceptibility Among Asians: A Systematic Review and Meta-Analysis.
Rezaee, M, Akbari, H, Momeni-Moghaddam, MA, Moazzen, F, Salahi, S, Jahankhah, R, Tahmasebi, S
Biochemical genetics. 2021;(2):367-397
Abstract
This systematic review and meta-analysis were conducted to investigate the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with breast cancer (BC) in Asians. Systematic searches were conducted in PubMed, EMBASE, Web of Science, and Scopus by May 2020. Inter-study heterogeneity was also assessed with a Q test, along with I2 statistics. Random-effects models were applied to pooled crude ORs with corresponding 95% CIs for the genetic models. A total of 1097 identified results, along with 36 qualified studies were included: for MTHFR C677T polymorphism, a total of 36 studies was comprised of 11,261 cases and 13,318 controls and for MTHFR A1298C polymorphism, a number of 19 studies contained 7424 cases and 8204 controls. Likewise, for C677T polymorphism, an increased risk of BC was seen for the allelic (OR 1.21, 95% CI 1.09-1.33, P < 0.01, I2 = 78.9%), dominant (OR 1.17, 95% CI 1.05-1.30, P < 0.01, I2 = 71.8%), recessive (OR 1.43, 95% CI 1.23-1.67, P < 0.01, I2 = 55.8%), and homozygous models (OR 1.48, 95% CI 1.25-1.75, P < 0.01, I2 59.9%) among BC patients compared to controls. Also, in terms of A1298C polymorphism, an association was found between the allelic (OR 1.15, 95% CI 1.04-1.28, P < 0.01, I2 70.4%) and homozygous models (OR 1.38, 95% CI 1.15-1.66, P < 0.01, I2 44.2%) with the risk of BC. In conclusion, findings revealed that MTHFR C677T variant might be a factor that predisposes BC in Asians. Furthermore, it was found that A1298C variant acts as a BC risk factor, particularly in a Western Asia population.
-
10.
Inhibition of calcitriol inactivating enzyme CYP24A1 gene expression by flavonoids in hepatocellular carcinoma cells under normoxia and hypoxia.
Angeli-Terzidou, AE, Gkotinakou, IM, Pazaitou-Panayiotou, K, Tsakalof, A
Archives of biochemistry and biophysics. 2021;:108889
Abstract
A vast number of epidemiological, preclinical and in vitro experimental data strongly indicate the anticancer potential of calcitriol, the biologically active form of vitamin D. However, for the implementation of a vitamin D based cancer therapy the increased deactivation of calcitriol in cancer cells by overexpressed CYP24A1 hydroxylase should be suppressed. Inhibition of this enzyme expression or activity nowadays is considered as important aspect of anticancer therapeutic strategies. Herein, we investigated the impact of genistein, biochanin A, formonentin and kaempferol on the expression of the CYP24A1 gene induced by calcitriol in hepatocellular cancer cells Huh7 under normoxia (21%O2) or hypoxia (1%O2). We demonstrate that calcitriol induces CYP24A1 under normoxia and hypoxia, but this induction is significantly more potent under hypoxia, the typical microenvironment of solid tumors. In the presence of isoflavones genistein, biochanin A and formononetin, this induction is abrogated to the control levels under normoxia, while under hypoxia there is some differentiation in suppression efficacy between these compounds with genistein ≥ biochanin > formononetin. At the same time, kaempferol turned out to be completely ineffective in the suppression of CYP24A1 gene expression.