bims-kracam 2021-08-22 papers

on K-Ras in cancer metabolism

Issue of 2021–08–22
eightteen papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development

The Crucial Roles of Intermediate Metabolites in Cancer.
Matrix stiffness primes cells for future oxidative stress.
Autophagy is a major metabolic regulator involved in cancer therapy resistance.
Metabolic convergence on lipogenesis in RAS, BCR-ABL, and MYC-driven lymphoid malignancies.
Metabolic Alterations in Preneoplastic Development Revealed by Untargeted Metabolomic Analysis.
Fructose in the diet expands the surface of the gut and promotes nutrient absorption.
Vitamin D and the risk for cancer: a molecular analysis.
Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy.
Vitamin D in Autophagy Signaling for Health and Diseases: Insights on Potential Mechanisms and Future Perspectives.
Metabolic decisions in development and disease-a Keystone Symposia report.
Dietary fructose improves intestinal cell survival and nutrient absorption.
Acetate Promotes a Differential Energy Metabolic Response in Human HCT 116 and COLO 205 Colon Cancer Cells Impacting Cancer Cell Growth and Invasiveness.
EGCG inhibits growth of tumoral lesions on lip and tongue of K-Ras transgenic mice through the Notch pathway.
Curcumin Inhibition of TGFβ signaling in bone metastatic breast cancer cells and the possible role of oxidative metabolites.
On target: Rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma.
Mutations of p53 associated with pancreatic cancer and therapeutic implications.
Phytochemicals: Targeting Mitophagy to Treat Metabolic Disorders.
Characterization of Histone Deacetylase Mechanisms in Cancer Development.

Cancer Manag Res. 2021 ;13 6291-6307

The Crucial Roles of Intermediate Metabolites in Cancer.

Sisi Huang, Zhiqin Wang, Liang Zhao.

  Metabolic alteration, one of the hallmarks of cancer cells, is important for cancer initiation and development. To support their rapid growth, cancer cells alter their metabolism so as to obtain the necessary energy and building blocks for biosynthetic pathways, as well as to adjust their redox balance. Once thought to be merely byproducts of metabolic pathways, intermediate metabolites are now known to mediate epigenetic modifications and protein post-transcriptional modifications (PTM), as well as connect cellular metabolism with signal transduction. Consequently, they can affect a myriad of processes, including proliferation, apoptosis, and immunity. In this review, we summarize multiple representative metabolites involved in glycolysis, the pentose phosphate pathway (PPP), the tricarboxylic acid (TCA) cycle, lipid synthesis, ketogenesis, methionine metabolism, glutamine metabolism, and tryptophan metabolism, focusing on their roles in chromatin and protein modifications and as signal-transducing messengers.

Keywords:  epigenetic modification; extra-metabolic functions; oncometabolites; post-transcriptional modifications; signaling transduction

DOI:  https://doi.org/10.2147/CMAR.S321433
Trends Cancer. 2021 Aug 17. pii: S2405-8033(21)00162-X. [Epub ahead of print]

Matrix stiffness primes cells for future oxidative stress.

Paul V Taufalele, Cynthia A Reinhart-King.

  Focus on metabolic reprogramming has re-emerged in recent years due to the far-reaching consequences of metabolism on nearly all cellular behaviors. In a recent study in Cell Metabolism, Tharp et al. show that adhesion-dependent mechanical signaling induces mitochondrial and metabolic reprogramming to help cells adapt to future oxidative stress.

Keywords:  ROS; matrix stiffness; mechanosignaling; mitohormesis

DOI:  https://doi.org/10.1016/j.trecan.2021.08.003
Cell Rep. 2021 Aug 17. pii: S2211-1247(21)00959-1. [Epub ahead of print]36(7): 109528

Autophagy is a major metabolic regulator involved in cancer therapy resistance.

Laura Poillet-Perez, Jean-Emmanuel Sarry, Carine Joffre.

  Autophagy sustains cellular homeostasis and metabolism in numerous diseases. By regulating cancer metabolism, both tumor and microenvironmental autophagy promote tumor growth. However, autophagy can support cancer progression through other biological functions such as immune response regulation or cytokine/growth factor secretion. Moreover, autophagy is induced in numerous tumor types as a resistance mechanism following therapy, highlighting autophagy inhibition as a promising target for anti-cancer therapy. Thus, better understanding the mechanisms involved in tumor growth and resistance regulation through autophagy, which are not fully understood, will provide insights into patient treatment.

Keywords:  Poillet-Perez et al. review how both tumor and microenvironmental autophagy promote tumor growth by regulating cancer metabolism and the immune response. Moreover; autophagy is induced as a cell death or resistance mechanism following therapy. Better understanding the role of autophagy and the mechanisms involved will provide insights into patient treatment

DOI:  https://doi.org/10.1016/j.celrep.2021.109528
Cancer Metab. 2021 Aug 16. 9(1): 31

Metabolic convergence on lipogenesis in RAS, BCR-ABL, and MYC-driven lymphoid malignancies.

Daniel F Liefwalker, Meital Ryan, Zhichao Wang, Khyatiben V Pathak, Seema Plaisier, Vidhi Shah, Bobby Babra, Gabrielle S Dewson, Ian K Lai, Adriane R Mosley, Patrick T Fueger, Stephanie C Casey, Lei Jiang, Patrick Pirrotte, Srividya Swaminathan, Rosalie C Sears.

   BACKGROUND: Metabolic reprogramming is a central feature in many cancer subtypes and a hallmark of cancer. Many therapeutic strategies attempt to exploit this feature, often having unintended side effects on normal metabolic programs and limited efficacy due to integrative nature of metabolic substrate sourcing. Although the initiating oncogenic lesion may vary, tumor cells in lymphoid malignancies often share similar environments and potentially similar metabolic profiles. We examined cells from mouse models of MYC-, RAS-, and BCR-ABL-driven lymphoid malignancies and find a convergence on de novo lipogenesis. We explore the potential role of MYC in mediating lipogenesis by 13C glucose tracing and untargeted metabolic profiling. Inhibition of lipogenesis leads to cell death both in vitro and in vivo and does not induce cell death of normal splenocytes.
METHODS: We analyzed RNA-seq data sets for common metabolic convergence in lymphoma and leukemia. Using in vitro cell lines derived in from conditional MYC, RAS, and BCR-ABL transgenic murine models and oncogene-driven human cell lines, we determined gene regulation, metabolic profiles, and sensitivity to inhibition of lipogenesis in lymphoid malignancies. We utilize preclinical murine models and transgenic primary model of T-ALL to determine the effect of lipogenesis blockade across BCR-ABL-, RAS-, and c-MYC-driven lymphoid malignancies. Statistical significance was calculated using unpaired t-tests and one-way ANOVA.
RESULTS: This study illustrates that de novo lipid biogenesis is a shared feature of several lymphoma subtypes. Using cell lines derived from conditional MYC, RAS, and BCR-ABL transgenic murine models, we demonstrate shared responses to inhibition of lipogenesis by the acetyl-coA carboxylase inhibitor 5-(tetradecloxy)-2-furic acid (TOFA), and other lipogenesis inhibitors. We performed metabolic tracing studies to confirm the influence of c-MYC and TOFA on lipogenesis. We identify specific cell death responses to TOFA in vitro and in vivo and demonstrate delayed engraftment and progression in vivo in transplanted lymphoma cell lines. We also observe delayed progression of T-ALL in a primary transgenic mouse model upon TOFA administration. In a panel of human cell lines, we demonstrate sensitivity to TOFA treatment as a metabolic liability due to the general convergence on de novo lipogenesis in lymphoid malignancies driven by MYC, RAS, or BCR-ABL. Importantly, cell death was not significantly observed in non-malignant cells in vivo.
CONCLUSIONS: These studies suggest that de novo lipogenesis may be a common survival strategy for many lymphoid malignancies and may be a clinically exploitable metabolic liability.
TRIAL REGISTRATION: This study does not include any clinical interventions on human subjects.

Keywords:  ACACA; BCR-ABL; Cancer metabolism; De novo lipogenesis; FASN; Fatty acid synthesis; Lipogenesis; Lymphoma; Oncogene addiction; RAS; T-ALL; c-MYC

DOI:  https://doi.org/10.1186/s40170-021-00263-8
Front Cell Dev Biol. 2021 ;9 684036

Metabolic Alterations in Preneoplastic Development Revealed by Untargeted Metabolomic Analysis.

Henna Myllymäki, Jeanette Astorga Johansson, Estefania Grados Porro, Abigail Elliot, Tessa Moses, Yi Feng.

  Metabolic rewiring is a critical hallmark of tumorigenesis and is essential for the development of cancer. Although many key features of metabolic alteration that are crucial for tumor cell survival, proliferation and progression have been identified, these are obtained from studies with established tumors and cancer cell lines. However, information on the essential metabolic changes that occur during pre-neoplastic cell (PNC) development that enables its progression to full blown tumor is still lacking. Here, we present an untargeted metabolomics analysis of human oncogene HRASG12V induced PNC development, using a transgenic inducible zebrafish larval skin development model. By comparison with normal sibling controls, we identified six metabolic pathways that are significantly altered during PNC development in the skin. Amongst these altered pathways are pyrimidine, purine and amino acid metabolism that are common to the cancer metabolic changes that support rapid cell proliferation and growth. Our data also suggest alterations in post transcriptional modification of RNAs that might play a role in PNC development. Our study provides a proof of principle work flow for identifying metabolic alterations during PNC development driven by an oncogenic mutation. In the future, this approach could be combined with transcriptomic or proteomic approaches to establish the detailed interaction between signaling networks and cellular metabolic pathways that occur at the onset of tumor progression.

Keywords:  HRAS; cancer metabolism; metabolome; preneoplastic; untargeted metabolomics; zebrafish

DOI:  https://doi.org/10.3389/fcell.2021.684036
Nature. 2021 Aug 18.

Fructose in the diet expands the surface of the gut and promotes nutrient absorption.

Patrícia M Nunes, Dimitrios Anastasiou.



Keywords:  Medical research; Metabolism

DOI:  https://doi.org/10.1038/d41586-021-02195-1
Biochem Pharmacol. 2021 Aug 16. pii: S0006-2952(21)00351-8. [Epub ahead of print] 114735

Vitamin D and the risk for cancer: a molecular analysis.

Carsten Carlberg, Eunike Velleuer.

  Uncontrolled overgrowth of cells, such as in cancer, is an unavoidable risk in life that affects nearly every second individual in industrialized countries. However, in part this risk can be controlled through lifestyle adjustments, such as the avoidance of smoking, unhealthy diet, obesity, physical inactivity and other cancer risk factors. A low vitaminD status is a risk in particular for cancers of colon, prostate, breast and leukocytes. VitaminD3 is produced non-enzymatically, when the cholesterol precursor 7-dehydrocholesterol is exposed to UV-B from sunlight, i.e., all cholesterol synthesizing species, including humans, can make vitaminD3. VitaminD endocrinology started some 550million years ago, when the metabolite 1α,25-dihydroxyvitaminD3 and the transcription factor vitaminD receptor teamed up for regulating the expression of hundreds of target genes in a multitude of different tissues and cell types. Initially, these genes were focused on the control of energy homeostasis, which later also involved energy-demanding innate and adaptive immunity. Rapidly growing cells of the immune system as well as those of malignant tumors rely on comparable genes and pathways, some of which are modulated by vitaminD. Accordingly, vitaminD has anti-cancer effects both directly via controling the differentiation, proliferation and apoptosis of neoplastic cells as well as indirectly through regulating immune cells that belong to the microenvironment of malignant tumors. This review discusses effects of vitaminD on the epigenome and transcriptome of stromal and tumor cells, inter-individual variations in vitaminD responsiveness and their relation to the prevention and possible therapy of cancer.

Keywords:  Cancer prevention; Colon cancer; Epigenome; Evolution; Immune system; Transcriptome; VDR; Vitamin D; Vitamin D response index; Vitamin D status; Vitamin D target genes

DOI:  https://doi.org/10.1016/j.bcp.2021.114735
J Cancer. 2021 ;12(18): 5543-5561

Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy.

Run Huang, Huan Chen, Jiayu Liang, Yi Li, Jiali Yang, Chuang Luo, Youshan Tang, Yu Ding, Xing Liu, Qing Yuan, Hong Yu, Yingchun Ye, Wenfeng Xu, Xiang Xie.

  Reactive oxygen species (ROS) play a dual role in the initiation, development, suppression, and treatment of cancer. Excess ROS can induce nuclear DNA, leading to cancer initiation. Not only that, but ROS also inhibit T cells and natural killer cells and promote the recruitment and M2 polarization of macrophages; consequently, cancer cells escape immune surveillance and immune defense. Furthermore, ROS promote tumor invasion and metastasis by triggering epithelial-mesenchymal transition in tumor cells. Interestingly, massive accumulation of ROS inhibits tumor growth in two ways: (1) by blocking cancer cell proliferation by suppressing the proliferation signaling pathway, cell cycle, and the biosynthesis of nucleotides and ATP and (2) by inducing cancer cell death via activating endoplasmic reticulum stress-, mitochondrial-, and P53- apoptotic pathways and the ferroptosis pathway. Unfortunately, cancer cells can adapt to ROS via a self-adaption system. This review highlighted the bidirectional regulation of ROS in cancer. The study further discussed the application of massively accumulated ROS in cancer treatment. Of note, the dual role of ROS in cancer and the self-adaptive ability of cancer cells should be taken into consideration for cancer prevention.

Keywords:  anti-cancer; cancer; pro-tumor; reactive oxygen species; self-adaption system; therapy

DOI:  https://doi.org/10.7150/jca.54699
J Nutr Biochem. 2021 Aug 14. pii: S0955-2863(21)00261-8. [Epub ahead of print] 108841

Vitamin D in Autophagy Signaling for Health and Diseases: Insights on Potential Mechanisms and Future Perspectives.

Sujit K Bhutia.

  Vitamin D regulates the pleiotropic effect to maintain cellular homeostasis and epidemiological evidence establishes an association between vitamin D deficiency and various human diseases. Here, the role of autophagy, the cellular self-degradation process, in vitamin D-dependent function is documented in different cellular settings and discussed the molecular aspects for treating chronic inflammatory, infectious diseases, and cancer. Vitamin D activates autophagy through a genomic and non-genomic signaling pathway to influence a wide variety of physiological functions of different body organs along with bone health and calcium metabolism. Moreover, it induces autophagy as a protective mechanism to inhibit oxidative stress and apoptosis to regulate cell proliferation, differentiation, and immune modulation. Furthermore, vitamin D and its receptor regulate autophagy signaling to control inflammation and host immunity by activating antimicrobial defense mechanisms. Vitamin D has been revealed as a potent anticancer agent and induces autophagy to increase the response to radiation and chemotherapeutic drugs for potential cancer therapy. Increasing vitamin D levels in the human body through timely exposure to sunlight or vitamin D supplements could activate autophagy as part of the homeostasis mechanism to prevent multiple human diseases and aging-associated dysfunctions.

Keywords:  Autophagy; Cancer; Immunity; Inflammation; Oxidative stress; Vitamin D

DOI:  https://doi.org/10.1016/j.jnutbio.2021.108841
Ann N Y Acad Sci. 2021 Aug 19.

Metabolic decisions in development and disease-a Keystone Symposia report.

Jennifer Cable, Olivier Pourquié, Kathryn E Wellen, Lydia W S Finley, Alexander Aulehla, Alex P Gould, Aurelio Teleman, William B Tu, Wendy Sarah Garrett, Irene Miguel-Aliaga, Norbert Perrimon, Lora V Hooper, A J Marian Walhout, Wei Wei, Theodore Alexandrov, Ayelet Erez, Markus Ralser, Joshua D Rabinowitz, Anupama Hemalatha, Paula Gutiérrez-Pérez, Navdeep S Chandel, Jared Rutter, Jason W Locasale, Juan C Landoni, Heather Christofk.

  There is an increasing appreciation for the role of metabolism in cell signaling and cell decision making. Precise metabolic control is essential in development, as evident by the disorders caused by mutations in metabolic enzymes. The metabolic profile of cells is often cell-type specific, changing as cells differentiate or during tumorigenesis. Recent evidence has shown that changes in metabolism are not merely a consequence of changes in cell state but that metabolites can serve to promote and/or inhibit these changes. Metabolites can link metabolic pathways with cell signaling pathways via several mechanisms, for example, by serving as substrates for protein post-translational modifications, by affecting enzyme activity via allosteric mechanisms, or by altering epigenetic markers. Unraveling the complex interactions governing metabolism, gene expression, and protein activity that ultimately govern a cell's fate will require new tools and interactions across disciplines. On March 24 and 25, 2021, experts in cell metabolism, developmental biology, and human disease met virtually for the Keystone eSymposium, "Metabolic Decisions in Development and Disease." The discussions explored how metabolites impact cellular and developmental decisions in a diverse range of model systems used to investigate normal development, developmental disorders, dietary effects, and cancer-mediated changes in metabolism.

Keywords:  cell signaling; development; inborn errors of metabolism; metabolism; metabolome; stem cell differentiation

DOI:  https://doi.org/10.1111/nyas.14678
Nature. 2021 Aug 18.

Dietary fructose improves intestinal cell survival and nutrient absorption.

Samuel R Taylor, Shakti Ramsamooj, Roger J Liang, Alyna Katti, Rita Pozovskiy, Neil Vasan, Seo-Kyoung Hwang, Navid Nahiyaan, Nancy J Francoeur, Emma M Schatoff, Jared L Johnson, Manish A Shah, Andrew J Dannenberg, Robert P Sebra, Lukas E Dow, Lewis C Cantley, Kyu Y Rhee, Marcus D Goncalves.

Fructose consumption is linked to the rising incidence of obesity and cancer, which are two of the leading causes of morbidity and mortality globally1,2. Dietary fructose metabolism begins at the epithelium of the small intestine, where fructose is transported by glucose transporter type 5 (GLUT5; encoded by SLC2A5) and phosphorylated by ketohexokinase to form fructose 1-phosphate, which accumulates to high levels in the cell3,4. Although this pathway has been implicated in obesity and tumour promotion, the exact mechanism that drives these pathologies in the intestine remains unclear. Here we show that dietary fructose improves the survival of intestinal cells and increases intestinal villus length in several mouse models. The increase in villus length expands the surface area of the gut and increases nutrient absorption and adiposity in mice that are fed a high-fat diet. In hypoxic intestinal cells, fructose 1-phosphate inhibits the M2 isoform of pyruvate kinase to promote cell survival5-7. Genetic ablation of ketohexokinase or stimulation of pyruvate kinase prevents villus elongation and abolishes the nutrient absorption and tumour growth that are induced by feeding mice with high-fructose corn syrup. The ability of fructose to promote cell survival through an allosteric metabolite thus provides additional insights into the excess adiposity generated by a Western diet, and a compelling explanation for the promotion of tumour growth by high-fructose corn syrup.

DOI: https://doi.org/10.1038/s41586-021-03827-2
Front Oncol. 2021 ;11 697408

Acetate Promotes a Differential Energy Metabolic Response in Human HCT 116 and COLO 205 Colon Cancer Cells Impacting Cancer Cell Growth and Invasiveness.

Sara Rodríguez-Enríquez, Diana Xochiquetzal Robledo-Cadena, Juan Carlos Gallardo-Pérez, Silvia Cecilia Pacheco-Velázquez, Citlali Vázquez, Emma Saavedra, Jorge Luis Vargas-Navarro, Betsy Alejandra Blanco-Carpintero, Álvaro Marín-Hernández, Ricardo Jasso-Chávez, Rusely Encalada, Luz Ruiz-Godoy, José Luis Aguilar-Ponce, Rafael Moreno-Sánchez.

  Under dysbiosis, a gut metabolic disorder, short-chain carboxylic acids (SCCAs) are secreted to the lumen, affecting colorectal cancer (CRC) development. Butyrate and propionate act as CRC growth inhibitors, but they might also serve as carbon source. In turn, the roles of acetate as metabolic fuel and protein acetylation promoter have not been clearly elucidated. To assess whether acetate favors CRC growth through active mitochondrial catabolism, a systematic study evaluating acetate thiokinase (AcK), energy metabolism, cell proliferation, and invasiveness was performed in two CRC cell lines incubated with physiological SCCAs concentrations. In COLO 205, acetate (+glucose) increased the cell density (50%), mitochondrial protein content (3-10 times), 2-OGDH acetylation, and oxidative phosphorylation (OxPhos) flux (36%), whereas glycolysis remained unchanged vs. glucose-cultured cells; the acetate-induced OxPhos activation correlated with a high AcK activity, content, and acetylation (1.5-6-fold). In contrast, acetate showed no effect on HCT116 cell growth, OxPhos, AcK activity, protein content, and acetylation. However, a substantial increment in the HIF-1α content, HIF-1α-glycolytic protein targets (1-2.3 times), and glycolytic flux (64%) was observed. Butyrate and propionate decreased the growth of both CRC cells by impairing OxPhos flux through mitophagy and mitochondrial fragmentation activation. It is described, for the first time, the role of acetate as metabolic fuel for ATP supply in CRC COLO 205 cells to sustain proliferation, aside from its well-known role as protein epigenetic regulator. The level of AcK determined in COLO 205 cells was similar to that found in human CRC biopsies, showing its potential role as metabolic marker.

Keywords:  acetate thiokinase; acetylation; cancer biomarker; colon cancer; oxidative phoshorylation

DOI:  https://doi.org/10.3389/fonc.2021.697408
J Nutr Biochem. 2021 Aug 15. pii: S0955-2863(21)00263-1. [Epub ahead of print] 108843

EGCG inhibits growth of tumoral lesions on lip and tongue of K-Ras transgenic mice through the Notch pathway.

Hua Wei, Qi Ge, Ling-Yu Zhang, Jing Xie, Rui-Huan Gan, You-Guang Lu, Da-Li Zheng.

  Epigallocatechin-3-gallate (EGCG), the main active ingredient of green tea, exhibits low toxic side effect and versatile bioactivities, and its anti-cancer effect has been extensively studied. Most of the studies used cancer cell lines and xenograft models. However, whether EGCG can prevent tumor onset after cancer associated mutations occur is still controversial. In the present study, Krt14-cre/ERT-Kras transgenic mice were developed and the expression of K-RasG12D was induced by tamoxifen. Two weeks after induction, the K-Ras mutant mice developed exophytic tumoral lesions on the lips and tongues, with significant activation of Notch signaling pathway. Administration of EGCG effectively delayed the time of appearance, decreased the size and weight of tumoral lesions, relieved heterotypic hyperplasia of tumoral lesions, and prolonged the life of the mice. The Notch signaling pathway was significantly inhibited by EGCG in the tumoral lesions. Furthermore, EGCG significantly induced cell apoptosis and inhibited the proliferation of tongue cancer cells by blocking the activation of Notch signaling pathway. Taken together, these results indicate EGCG as an effective chemotherapeutic agent for tongue cancer by targeting Notch pathway.

Keywords:  EGCG; KRas mutation; Notch signaling pathway; tongue squamous cell carcinoma

DOI:  https://doi.org/10.1016/j.jnutbio.2021.108843
J Nutr Biochem. 2021 Aug 15. pii: S0955-2863(21)00262-X. [Epub ahead of print] 108842

Curcumin Inhibition of TGFβ signaling in bone metastatic breast cancer cells and the possible role of oxidative metabolites.

Andrew G Kunihiro, Julia A Brickey, Jennifer B Frye, Julia N Cheng, Paula B Luis, Claus Schneider, Janet L Funk.

  TGFβ signaling promotes progression of bone-metastatic (BMET) breast cancer (BCa) cells by driving tumor-associated osteolysis, a hallmark of BCa BMETs, thus allowing for tumor expansion within bone. Turmeric-derived bioactive curcumin, enriched in bone via local enzymatic deconjugation of inactive circulating curcumin-glucuronides, inhibits osteolysis and BMET progression in human xenograft BCa BMET models by blocking tumoral TGFβ signaling pathways mediating osteolysis. This is a unique anti-osteolytic mechanism in contrast to current osteoclast-targeting therapeutics. Therefore, experiments were undertaken to elucidate the mechanism for curcumin inhibition of BCa TGFβ signaling and the application of this finding across multiple BCa cell lines forming TGFβ-dependent BMETs, including a possible role for bioactive curcumin metabolites in mediating these effects. Immunoblot analysis of TGFβ signaling proteins in bone tropic human (MDA-SA, MDA-1833, MDA-2287) and murine (4T1) BCa cells revealed uniform curcumin blockade of TGFβ-induced Smad activation due to down-regulation of plasma membrane associated TGFβR2 and cellular receptor Smad proteins that propagate Smad-mediated gene expression, resulting in downregulation of PTHrP expression, the osteolytic factor driving in vivo BMET progression. With the exception of early decreases in TGFβR2, inhibitory effects appeared to be mediated by oxidative metabolites of curcumin and involved inhibition of gene expression. Interestingly, while not contributing to changes in Smad-mediated TGFβ signaling, curcumin caused early activation of MAPK signaling in all cell lines, including JNK, an effect possibly involving interactions with TGFβR2 within lipid rafts. Treatment with curcumin or oxidizable analogs of curcumin may have clinical relevancy in the management of TGFβ-dependent BCa BMETs.

Keywords:  Bone metastases; Breast cancer; Curcumin; JNK; Smad; TGFβ

DOI:  https://doi.org/10.1016/j.jnutbio.2021.108842
Lung Cancer. 2021 Jul 16. pii: S0169-5002(21)00474-8. [Epub ahead of print]

On target: Rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma.

Colin R Lindsay, Marina C Garassino, Ernest Nadal, Katarina Öhrling, Matthias Scheffler, Julien Mazières.

  Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer death. Approximately one-third of patients with NSCLC have a KRAS mutation. KRASG12C, the most common mutation, is found in ~13% of patients. While KRAS was long considered 'undruggable', several novel direct KRASG12C inhibitors have shown encouraging signs of efficacy in phase I/II trials and one of these (sotorasib) has recently been approved by the US Food and Drug Administration. This review examines the role of KRAS mutations in NSCLC and the challenges in targeting KRAS. Based on specific KRAS biology, it reports exciting progress, exploring the use of novel direct KRAS inhibitors as monotherapy or in combination with other targeted therapies, chemotherapy, and immunotherapy.

Keywords:  G12C; Immunotherapy; Lung cancer; Oncogene; Targeted therapy

DOI:  https://doi.org/10.1016/j.lungcan.2021.07.005
Ann Hepatobiliary Pancreat Surg. 2021 Aug 31. 25(3): 315-327

Mutations of p53 associated with pancreatic cancer and therapeutic implications.

Ioannis A Voutsadakis.

  Pancreatic adenocarcinoma is a malignancy with rising incidence and grim prognosis. Despite improvements in therapeutics for treating metastatic pancreatic cancer, this disease is invariably fatal with survival time less than a few years. New molecular understanding of the pathogenesis of pancreatic adenocarcinoma based on efforts led by The Cancer Genome Atlas and other groups has elucidated the landscape of this disease and started to produce therapeutic results, leading to the first introduction of targeted therapies for subsets of pancreatic cancers bearing specific molecular lesions such as BRCA mutations. These efforts have highlighted that subsets of pancreatic cancers are particularly sensitive to chemotherapy. The most common molecular lesions in pancreatic adenocarcinomas are mutations in an oncogene KRAS and the TP53 gene that encodes for tumor suppressor protein p53. This paper will review the landscape of pancreatic cancers, focusing on mutations of p53, a major tumor suppressor protein, in pancreatic cancers and possible therapeutic repercussions.

Keywords:  Gain of function; Mutation; Pancreatic adenocarcinoma; TP53; Targeted therapies

DOI:  https://doi.org/10.14701/ahbps.2021.25.3.315
Front Cell Dev Biol. 2021 ;9 686820

Phytochemicals: Targeting Mitophagy to Treat Metabolic Disorders.

Zuqing Su, Yanru Guo, Xiufang Huang, Bing Feng, Lipeng Tang, Guangjuan Zheng, Ying Zhu.

  Metabolic disorders include metabolic syndrome, obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease and cardiovascular diseases. Due to unhealthy lifestyles such as high-calorie diet, sedentary and physical inactivity, the prevalence of metabolic disorders poses a huge challenge to global human health, which is the leading cause of global human death. Mitochondrion is the major site of adenosine triphosphate synthesis, fatty acid β-oxidation and ROS production. Accumulating evidence suggests that mitochondrial dysfunction-related oxidative stress and inflammation is involved in the development of metabolic disorders. Mitophagy, a catabolic process, selectively degrades damaged or superfluous mitochondria to reverse mitochondrial dysfunction and preserve mitochondrial function. It is considered to be one of the major mechanisms responsible for mitochondrial quality control. Growing evidence shows that mitophagy can prevent and treat metabolic disorders through suppressing mitochondrial dysfunction-induced oxidative stress and inflammation. In the past decade, in order to expand the range of pharmaceutical options, more and more phytochemicals have been proven to have therapeutic effects on metabolic disorders. Many of these phytochemicals have been proved to activate mitophagy to ameliorate metabolic disorders. Given the ongoing epidemic of metabolic disorders, it is of great significance to explore the contribution and underlying mechanisms of mitophagy in metabolic disorders, and to understand the effects and molecular mechanisms of phytochemicals on the treatment of metabolic disorders. Here, we investigate the mechanism of mitochondrial dysfunction in metabolic disorders and discuss the potential of targeting mitophagy with phytochemicals for the treatment of metabolic disorders, with a view to providing a direction for finding phytochemicals that target mitophagy to prevent or treat metabolic disorders.

Keywords:  inflammatory response; metabolic disorders; mitochondrial dysfunction; mitophagy; oxidative stress; phytochemicals

DOI:  https://doi.org/10.3389/fcell.2021.686820
Front Oncol. 2021 ;11 700947

Characterization of Histone Deacetylase Mechanisms in Cancer Development.

Rihan Hai, Liuer He, Guang Shu, Gang Yin.

  Over decades of studies, accumulating evidence has suggested that epigenetic dysregulation is a hallmark of tumours. Post-translational modifications of histones are involved in tumour pathogenesis and development mainly by influencing a broad range of physiological processes. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are pivotal epigenetic modulators that regulate dynamic processes in the acetylation of histones at lysine residues, thereby influencing transcription of oncogenes and tumour suppressor genes. Moreover, HDACs mediate the deacetylation process of many nonhistone proteins and thus orchestrate a host of pathological processes, such as tumour pathogenesis. In this review, we elucidate the functions of HDACs in cancer.

Keywords:  cancer; epigenetics; histone deacetylases; protein acetylation; tumorigenesis

DOI:  https://doi.org/10.3389/fonc.2021.700947