bims-kracam 2021-06-27 papers

on K-Ras in cancer metabolism

Issue of 2021–06–27
thirteen papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development

Molecular and Metabolic Reprogramming: Pulling the Strings Toward Tumor Metastasis.
An update on methods and approaches for interrogating mitochondrial reactive oxygen species production.
The redox-senescence axis and its therapeutic targeting.
Mitochondrial metabolism regulates macrophage biology.
Protein tyrosine phosphatome metabolic screen identifies TC-PTP as a positive regulator of cancer cell bioenergetics and mitochondrial dynamics.
Trending topics of SIRT1 in tumorigenicity.
Cellular and metabolic mechanisms of nutrient actions in immune function.
A novel therapeutic strategy for hepatocellular carcinoma: Immunomodulatory mechanisms of selenium and/or selenoproteins on a shift towards anti-cancer.
mTORC1 Activation is Not Sufficient to Suppress Hepatic PPARα Signaling or Ketogenesis.
Perspectives for synthetic curcumins in chemoprevention and treatment of cancer: An update with promising analogues.
Effects of tetrahydrocannabinols on human oral cancer cell proliferation, apoptosis, autophagy, oxidative stress, and DNA damage.
Quercetin nanoformulations: a promising strategy for tumor therapy.
Recent progress on nanomedicine-induced ferroptosis for cancer therapy.

Front Oncol. 2021 ;11 656851

Molecular and Metabolic Reprogramming: Pulling the Strings Toward Tumor Metastasis.

Ana Hipólito, Filipa Martins, Cindy Mendes, Filipa Lopes-Coelho, Jacinta Serpa.

  Metastasis is a major hurdle to the efficient treatment of cancer, accounting for the great majority of cancer-related deaths. Although several studies have disclosed the detailed mechanisms underlying primary tumor formation, the emergence of metastatic disease remains poorly understood. This multistep process encompasses the dissemination of cancer cells to distant organs, followed by their adaptation to foreign microenvironments and establishment in secondary tumors. During the last decades, it was discovered that these events may be favored by particular metabolic patterns, which are dependent on reprogrammed signaling pathways in cancer cells while they acquire metastatic traits. In this review, we present current knowledge of molecular mechanisms that coordinate the crosstalk between metastatic signaling and cellular metabolism. The recent findings involving the contribution of crucial metabolic pathways involved in the bioenergetics and biosynthesis control in metastatic cells are summarized. Finally, we highlight new promising metabolism-based therapeutic strategies as a putative way of impairing metastasis.

Keywords:  metabolic reprogramming; metastasis; metastatic cascade; new therapies; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2021.656851
Redox Biol. 2021 Jun 16. pii: S2213-2317(21)00203-2. [Epub ahead of print]45 102044

An update on methods and approaches for interrogating mitochondrial reactive oxygen species production.

Ryan J Mailloux.

  The chief ROS formed by mitochondria are superoxide (O2·-) and hydrogen peroxide (H2O2). Superoxide is converted rapidly to H2O2 and therefore the latter is the chief ROS emitted by mitochondria into the cell. Once considered an unavoidable by-product of aerobic respiration, H2O2 is now regarded as a central mitokine used in mitochondrial redox signaling. However, it has been postulated that O2·- can also serve as a signal in mammalian cells. Progress in understanding the role of mitochondrial H2O2 in signaling is due to significant advances in the development of methods and technologies for its detection. Unfortunately, the development of techniques to selectively measure basal O2·- changes has been met with more significant hurdles due to its short half-life and the lack of specific probes. The development of sensitive techniques for the selective and real time measure of O2·- and H2O2 has come on two fronts: development of genetically encoded fluorescent proteins and small molecule reporters. In 2015, I published a detailed comprehensive review on the state of knowledge for mitochondrial ROS production and how it is controlled, which included an in-depth discussion of the up-to-date methods utilized for the detection of both superoxide (O2·-) and H2O2. In the article, I presented the challenges associated with utilizing these probes and their significance in advancing our collective understanding of ROS signaling. Since then, many other authors in the field of Redox Biology have published articles on the challenges and developments detecting O2·- and H2O2 in various organisms [1-3]. There has been significant advances in this state of knowledge, including the development of novel genetically encoded fluorescent H2O2 probes, several O2·- sensors, and the establishment of a toolkit of inhibitors and substrates for the interrogation of mitochondrial H2O2 production and the antioxidant defenses utilized to maintain the cellular H2O2 steady-state. Here, I provide an update on these methods and their implementation in furthering our understanding of how mitochondria serve as cell ROS stabilizing devices for H2O2 signaling.

Keywords:  Methods for measuring ROS; Mitochondria; Peroxide detectors; Reactive oxygen species; Superoxide probes

DOI:  https://doi.org/10.1016/j.redox.2021.102044
Redox Biol. 2021 Jun 05. pii: S2213-2317(21)00190-7. [Epub ahead of print]45 102032

The redox-senescence axis and its therapeutic targeting.

Natalie Yl Ngoi, Angeline Qx Liew, Stephen J F Chong, Matthew S Davids, Marie-Veronique Clement, Shazib Pervaiz.

   SIGNIFICANCE: Cellular growth arrest, associated with 'senescence', helps to safeguard against the accumulation of DNA damage which is often recognized as the underlying mechanism of a wide variety of age-related pathologies including cancer. Cellular senescence has also been described as a 'double-edged sword'. In cancer, for example, the creation of an immune-suppressive milieu by senescent tumor cells through the senescence-associated secretory phenotype contributes toward carcinogenesis and cancer progression.
RECENT ADVANCES: The potential for cellular senescence to confer multi-faceted effects on tissue fate has led to a rejuvenated interest in its landscape and targeting. Interestingly, redox pathways have been described as both triggers and propagators of cellular senescence, leading to intricate cross-links between both pathways.
CRITICAL ISSUES: In this review, we describe the mechanisms driving cellular senescence, the interface with cellular redox metabolism as well as the role that chemotherapy-induced senescence plays in secondary carcinogenesis. Notably, the role that anti-apoptotic proteins of the Bcl-2 family play in inducing drug resistance via mechanisms that involve senescence induction.
FUTURE DIRECTIONS: Though the therapeutic targeting of senescent cells as cancer therapy remains in its infancy, we summarize the current development of senotherapeutics, including recognized senotherapies, as well as the repurposing of drugs as senomorphic/senolytic candidates.

Keywords:  Cancer therapy; ROS; SASP; Senescence; Senolytics

DOI:  https://doi.org/10.1016/j.redox.2021.102032
J Biol Chem. 2021 Jun 19. pii: S0021-9258(21)00704-3. [Epub ahead of print] 100904

Mitochondrial metabolism regulates macrophage biology.

Yafang Wang, Na Li, Xin Zhang, Tiffany Horng.

  Mitochondria are critical for regulation of the activation, differentiation, and survival of macrophages and other immune cells. In response to various extracellular signals, such as microbial or viral infection, changes to mitochondrial metabolism and physiology could underlie the corresponding state of macrophage activation. These changes include alterations of oxidative metabolism, mitochondrial membrane potential, and tricarboxylic acid (TCA) cycling, as well as the release of mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA) and transformation of the mitochondrial ultrastructure. Here, we provide an updated review of how changes in mitochondrial metabolism and various metabolites such as fumarate, succinate, and itaconate coordinate to guide macrophage activation to distinct cellular states, thus clarifying the vital link between mitochondria metabolism and immunity. We also discuss how in disease settings, mitochondrial dysfunction and oxidative stress contribute to dysregulation of the inflammatory response. Therefore, mitochondria are a vital source of dynamic signals that regulate macrophage biology to fine-tune immune responses.

Keywords:  macrophage activation; macrophage biology; mitochondrial dysfunction; mitochondrial metabolism; oxidative stress

DOI:  https://doi.org/10.1016/j.jbc.2021.100904
FASEB J. 2021 Jul;35(7): e21708

Protein tyrosine phosphatome metabolic screen identifies TC-PTP as a positive regulator of cancer cell bioenergetics and mitochondrial dynamics.

Valerie Vinette, Isabelle Aubry, Hayley Insull, Noriko Uetani, Serge Hardy, Michel L Tremblay.

  Metabolic reprogramming occurs in cancer cells and is regulated partly by the opposing actions of tyrosine kinases and tyrosine phosphatases. Several members of the protein tyrosine phosphatase (PTP) superfamily have been linked to cancer as either pro-oncogenic or tumor-suppressive enzymes. In order to investigate which PTPs can modulate the metabolic state of cancer cells, we performed an shRNA screen of PTPs in HCT116 human colorectal cancer cells. Among the 72 PTPs efficiently targeted, 24 were found to regulate mitochondrial respiration, 8 as negative and 16 as positive regulators. Of the latter, we selected TC-PTP (PTPN2) for further characterization since inhibition of this PTP resulted in major functional defects in oxidative metabolism without affecting glycolytic flux. Transmission electron microscopy revealed an increase in the number of damaged mitochondria in TC-PTP-null cells, demonstrating the potential role of this PTP in regulating mitochondrial homeostasis. Downregulation of STAT3 by siRNA-mediated silencing partially rescued the mitochondrial respiration defect observed in TC-PTP-deficient cells, supporting the role of this signaling axis in regulating mitochondrial activity. In addition, mitochondrial stress prevented an increased expression of electron transport chain-related genes in cells with TC-PTP silencing, correlating with decreased ATP production, cellular proliferation, and migration. Our shRNA-based metabolic screen revealed that PTPs can serve as either positive or negative regulators of cancer cell metabolism. Taken together, our findings uncover a new role for TC-PTP as an activator of mitochondrial metabolism, validating this PTP as a key target for cancer therapeutics.

Keywords:  PTPN2; TC-PTP; cancer; metabolism; mitochondria; protein tyrosine phosphatases

DOI:  https://doi.org/10.1096/fj.202100207R
Biochim Biophys Acta Gen Subj. 2021 Jun 18. pii: S0304-4165(21)00110-0. [Epub ahead of print]1865(9): 129952

Trending topics of SIRT1 in tumorigenicity.

Liz M Garcia-Peterson, Xiaoling Li.

   BACKGROUND: Carcinogenesis is governed by a series of genetic alterations and epigenetic changes that lead to aberrant patterns in neoplastic cells. Sirtuin-1(SIRT1), an NAD+-dependent protein deacetylase, is capable of deacetylating histones and non-histone substrates that regulate various physiological activities during tumorigenesis. Recent studies have identified the role of SIRT1 in different stages of cancer, including genome instability, tumor initiation, proliferation, metabolism, and therapeutic response. However, the action of SIRT1 has been reported to be both oncogenic and tumor suppressive during carcinogenesis. Consequently, the biological functions of SIRT1 in cancer remain controversial.
SCOPE OF REVIEW: We highlight the most recent findings on SIRT1 in different stages of tumorigenesis, and update the current status of SIRT1 small molecule modulators in clinical application of cancer treatment.
MAJOR CONCLUSION: By targeting both tumor suppressors and oncogenic proteins, SIRT1 has a bifunctional role at different stages of tumorigenesis. The impact of SIRT1 on tumorigenesis is also distinct at different stages and is dependent on its dosages. SIRT1 suppresses tumor initiation through its functions in promoting DNA repair, increasing genome stability, and inhibiting inflammation at the pre-cancer stage. However, SIRT1 enhances tumor proliferation, survival, and drug resistance through its roles in anti-apoptosis, pro-tumor metabolism, and anti-inflammation (inhibition of anti-tumor immunity) at the stages of tumor progression, metastasis, and relapse. Consequently, both SIRT1 inhibitors and activators have been explored for cancer treatment.
GENERAL SIGNIFICANCE: Better understanding the dose- and stage-dependent roles of SIRT1 in each cancer type can provide new avenues of exploration for therapy development.

Keywords:  Bifunctional functions; Cancer; Cancer stem cell; Metabolism; SIRT1; Sirtuins; Therapeutic response

DOI:  https://doi.org/10.1016/j.bbagen.2021.129952
Nutr Diabetes. 2021 Jun 23. 11(1): 22

Cellular and metabolic mechanisms of nutrient actions in immune function.

Philip Newsholme.

Various nutrients can change cell structure, cellular metabolism, and cell function which is particularly important for cells of the immune system as nutrient availability is associated with the activation and function of diverse immune subsets. The most important nutrients for immune cell function and fate appear to be glucose, amino acids, fatty acids, and vitamin D. This perspective will describe recently published information describing the mechanism of action of prominent nutritional intervention agents where evidence exists as to their action and potency.

DOI: https://doi.org/10.1038/s41387-021-00162-3
Int Immunopharmacol. 2021 Jul;pii: S1567-5769(21)00426-4. [Epub ahead of print]96 107790

A novel therapeutic strategy for hepatocellular carcinoma: Immunomodulatory mechanisms of selenium and/or selenoproteins on a shift towards anti-cancer.

Bao-Kang Wu, Qian-Hui Chen, Dan Pan, Bing Chang, Li-Xuan Sang.

  Selenium (Se) is an essential trace chemical element that is widely distributed worldwide. Se exerts its immunomodulatory and nutritional activities in the human body in the form of selenoproteins. Se has increasingly appeared as a potential trace element associated with many human diseases, including hepatocellular carcinoma (HCC). Recently, increasing evidence has suggested that Se and selenoproteins exert their immunomodulatory effects on HCC by regulating the molecules of oxidative stress, inflammation, immune response, cell proliferation and growth, angiogenesis, signaling pathways, apoptosis, and other processes in vitro cell studies and in vivo animal studies. Se concentrations are generally low in tissues of patients with HCC, such as blood, serum, scalp hair, and toenail. However, Se concentrations were higher in HCC patient tissues after Se supplementation than before supplementation. This review summarizes the significant relationship between Se and HCC, and details the role of Se as a novel immunomodulatory or immunotherapeutic approach against HCC.

Keywords:  Bioavailability; Hepatocellular carcinoma; Immunomodulatory; Selenium

DOI:  https://doi.org/10.1016/j.intimp.2021.107790
J Biol Chem. 2021 Jun 16. pii: S0021-9258(21)00684-0. [Epub ahead of print] 100884

mTORC1 Activation is Not Sufficient to Suppress Hepatic PPARα Signaling or Ketogenesis.

Ebru S Selen, Michael J Wolfgang.

  The mechanistic target of rapamycin (mTOR) is often referred to as a master regulator of cellular metabolism that can integrate growth factor and nutrient signaling. Fasting suppresses hepatic mTORC1 activity via the activity of the Tuberous Sclerosis Complex (TSC), a negative regulator of mTORC1, in order to suppress anabolic metabolism. The loss of TSC1 in the liver locks the liver in a constitutively anabolic state even during fasting, which was suggested to regulate PPARα signaling and ketogenesis, but the molecular determinants of this regulation are unknown. Here, we examined if the activation of the mTORC1 complex in mice by the liver-specific deletion of TSC1 (TSC1L-/-) is sufficient to suppress PPARα signaling and therefore ketogenesis in the fasted state. We found that the activation of mTORC1 in the fasted state is not sufficient to repress PPARα-responsive genes or ketogenesis. Further, we examined whether the activation of the anabolic program mediated by mTORC1 complex activation in the fasted state could suppress the robust catabolic programming and enhanced PPARα transcriptional response of mice with a liver-specific defect in mitochondrial long-chain fatty acid oxidation using Cpt2L-/- mice. We generated liver-specific Cpt2L-/-; Tsc1L-/- double knockout mice and showed that the activation of mTORC1 by deletion of TSC1 could not suppress the catabolic PPARα-mediated phenotype of Cpt2L-/- mice. These data demonstrate that the activation of mTORC1 by the deletion of TSC1 is not sufficient to suppress a PPARα transcriptional program or ketogenesis following fasting.

Keywords:  Ketogenesis; carnitine palmitoyltransferase 2 (Cpt2); fatty acid oxidation; mTOR; metabolism; peroxisome proliferator-activated receptor alpha (PPARα); β-hydroxybutyrate (βHB)

DOI:  https://doi.org/10.1016/j.jbc.2021.100884
Eur J Pharmacol. 2021 Jun 17. pii: S0014-2999(21)00419-2. [Epub ahead of print]906 174266

Perspectives for synthetic curcumins in chemoprevention and treatment of cancer: An update with promising analogues.

Adeoluwa Adeluola, Abu Hasanat Md Zulfiker, Daniel Brazeau, A R M Ruhul Amin.

  Curcumin, a pure compound extracted from the flowering plant, turmeric (Curcuma longa. Zingiberaceae), is a common dietary ingredient found in curry powder. It has been studied extensively for its anti-inflammatory, antioxidant, antimicrobial and anti-tumour activities. Evidence is accumulating demonstrating its potential in chemoprevention and as an anti-tumour agent for the treatment of cancer. Despite demonstrated safety and tolerability, the clinical application of curcumin is frustrated by its poor solubility, metabolic instability and low oral bioavailability. Consequently researchers have tried novel techniques of formulation and delivery as well as synthesis of analogues with enhanced properties to overcome these barriers. This review presents the synthetic analogues of curcumin that have proven their anticancer potential from different studies. It also highlights studies that combined these analogues with approved chemotherapies and delivered them via novel techniques. Currently, there are no reports of clinical studies on any of the synthetic congeners of curcumin and this presents an opportunity for future research. This review presents the synthetic analogues of curcumin and makes a compelling argument for their potential application in the management of cancerous disease.

Keywords:  Apoptosis; Chemoprevention; Curcumin; Molecular targets; Synthetic analogues

DOI:  https://doi.org/10.1016/j.ejphar.2021.174266
Arch Oral Biol. 2021 Jun 16. pii: S0003-9969(21)00163-1. [Epub ahead of print]129 105200

Effects of tetrahydrocannabinols on human oral cancer cell proliferation, apoptosis, autophagy, oxidative stress, and DNA damage.

Abdelhabib Semlali, Sarra Beji, Ikram Ajala, Mahmoud Rouabhia.

   OBJECTIVE: Cannabinoids, including delta-8- and delta-9-tetrahydrocannabinol (THC) have a palliative care impact and may therefore be beneficial against cancer. The aim of this study was to investigate the effect of Δ9-THC and Δ8-THC on oral cancer cell behaviors.
DESIGN: The Ca9-22 oral cancer cells were cultured in the presence or not of various concentrations of Δ9-THC and Δ8-THC for different times. The cultures were then used to measure cell viability/proliferation, apoptosis, autophagy, oxidative stress, antioxidant activity, and inhibition of signaling pathways MAP-Kinase, NF-κB, and β-catenin.
RESULTS: Both cannabinoids were found to decrease cell viability/proliferation by blocking the cell cycle progression from the S to the G2/M phase and enhancing their apoptosis and autophagy. Δ9-THC and Δ8-THC also suppressed the migration/invasion by inhibiting epithelial-mesenchymal transition markers, such as E-cadherin, in addition to decreasing reactive oxygen species (ROS) production and increasing glutathione (GSH) and the expression of mtMP. Δ9-THC and Δ8-THC also downregulated cyclin D1, p53, NOXA, PUMAα, and DRAM expressions but increased p21 and H2AX expression.
CONCLUSION: We demonstrated that cannabinoids (Δ9-THC and Δ8-THC) were able to decrease oral cancer cell growth through various mechanisms, including apoptosis, autophagy, and oxidative stress. These results suggest a potential use of these molecules as a therapy against oral cancer.

Keywords:  Apoptosis; Autophagy; Cannabinoids; Oral cancer; Oxidative stress; Signaling pathways

DOI:  https://doi.org/10.1016/j.archoralbio.2021.105200
Food Funct. 2021 Jun 21.

Quercetin nanoformulations: a promising strategy for tumor therapy.

Xinlong Zang, Mingyang Cheng, Xiaoxu Zhang, Xuehong Chen.

Phytochemicals as dietary constituents are being widely explored for the prevention and treatment of various diseases. Quercetin, a major constituent of various dietary products, has attracted extensive interest due to its anti-proliferative capability, reversal of multidrug resistance, autophagy promotion and tumor microenvironment modulation on different cancer types. Although quercetin has shown potent medical value, its application as an antitumor drug is limited. Problems like poor solubility, bioavailability and stability, short half-life and weak tumor-targeting biodistribution make quercetin an unreliable candidate for cancer therapy. Nanoparticle based platforms have shown a number of advantages in delivering a hydrophobic drug like quercetin to diseased tissues. Quercetin nanoparticles have demonstrated high encapsulation efficiency, stability, sustained release, prolonged circulation time, improved accumulation at tumor sites and therapeutic efficiency. Moreover, a combination of quercetin with other diagnostic or therapeutic agents in one nanocarrier has achieved enhancements in detecting or treating tumors. In this review, we have tried to summarize the pharmacological activities of quercetin with regard to tumor cells and microenvironments in vitro and in vivo. Furthermore, various nanoformulations have been highlighted for quercetin delivery for cancer treatment. These results suggest that quercetin nanoparticles may be a promising antitumor therapeutic agent.

DOI: https://doi.org/10.1039/d1fo00851j
Biomater Sci. 2021 Jun 23.

Recent progress on nanomedicine-induced ferroptosis for cancer therapy.

Hajra Zafar, Faisal Raza, Siyu Ma, Yawen Wei, Jun Zhang, Qi Shen.

The current treatment strategies for cancer therapy have posed many problems in achieving high efficacy. Therefore, an urgent step is needed to develop innovative therapies that can win beyond satisfactory results against tumor. Ferroptosis that is a kind of non-apoptotic based programmed cell death has played a crucial role in eradicating tumors by reactive oxygen species and iron-dependent pathways. Research shows a remarkable potential of ferroptosis in eliminating aggressive malignancies resistant to traditional therapies. The combination of nanomedicine and ferroptosis has revealed a close relationship for the treatment of various cancer types with high efficacy. This review introduces the basics of nanomedicine-based ferroptosis first to emphasize the feasibility and properties of ferroptosis in cancer therapy. Then, the current research on the applications of nanomedicine for the ferroptosis-based anticancer therapy is highlighted. Finally, conclusions and future research directions in perspective of various challenges in developing nanomedicine-based ferroptosis into clinical therapeutics are discussed.

DOI: https://doi.org/10.1039/d1bm00721a