bims-cadres Biomed News
on Cancer drug resistance
Issue of 2022–08–07
nine papers selected by
Rana Gbyli, Yale University
  1. CASC9 potentiates gemcitabine resistance in pancreatic cancer by reciprocally activating NRF2 and the NF-κB signaling pathway.
  2. SOX15 transcriptionally increases the function of AOC1 to modulate ferroptosis and progression in prostate cancer.
  3. DCLK1 promotes colorectal cancer stemness and aggressiveness via the XRCC5/COX2 axis.
  4. A SOX2-engineered epigenetic silencer factor represses the glioblastoma genetic program and restrains tumor development.
  5. Ym155 localizes to the mitochondria leading to mitochondria dysfunction and activation of AMPK that inhibits BMP signaling in lung cancer cells.
  6. Metabolic reprogramming from glycolysis to fatty acid uptake and beta-oxidation in platinum-resistant cancer cells.
  7. Targeting SREBP-1-Mediated Lipogenesis as Potential Strategies for Cancer.
  8. Emerging metabolomic tools to study cancer metastasis.
  9. Metabolic reprogramming by adenosine antagonism and implications in non-small cell lung cancer therapy.
  1. Cell Biol Toxicol. 2022 Aug 01.
    CASC9 potentiates gemcitabine resistance in pancreatic cancer by reciprocally activating NRF2 and the NF-κB signaling pathway.
    Zhengle Zhang, Longjiang Chen, Chuanbing Zhao, Qiong Gong, Zhigang Tang, Hanjun Li, Jing Tao.
      Gemcitabine resistance is a frequently occurring and intractable obstacle in pancreatic cancer treatment. However, the underlying mechanisms require further investigation. Adaptive regulation of oxidative stress and aberrant activation of the NF-κB signaling pathway are associated with resistance to chemotherapy. Here, we found that gemcitabine upregulated the expression of CASC9 in a dose-dependent manner, partially via induction of reactive oxygen species, whereas inhibition of CASC9 expression enhanced gemcitabine-induced oxidative stress and apoptosis in pancreatic cancer cells. Furthermore, suppression of CASC9 level inhibited the expression of NRF2 and the downstream genes NQO1 and HO-1, and vice versa, indicating that CASC9 forms a positive feedback loop with NRF2 signaling and modulates the level of oxidative stress. Silencing CASC9 attenuated NF-κB pathway activation in pancreatic cancer cells and synergistically enhanced the cytotoxic effect of gemcitabine chemotherapy in vivo. In conclusion, our findings suggest that CASC9 plays a key role in driving resistance to gemcitabine through a reciprocal loop with the NRF2-antioxidant signaling pathway and by activating NF-κB signaling. Our study reveals potential targets that can effectively reverse resistance to gemcitabine chemotherapy.
    Keywords:  CASC9; Gemcitabine; NF-κB; NRF2; Oxidative stress; Pancreatic cancer
    DOI:  https://doi.org/10.1007/s10565-022-09746-w
  2. Cell Death Dis. 2022 Aug 03. 13(8): 673
    SOX15 transcriptionally increases the function of AOC1 to modulate ferroptosis and progression in prostate cancer.
    Yinghui Ding, Yuankang Feng, Zhenlin Huang, Yu Zhang, Xiang Li, Ruoyang Liu, Hao Li, Tao Wang, Yafei Ding, Zhankui Jia, Jinjian Yang.
      Amine oxidase copper-containing 1 (AOC1) is considered an oncogene in many types of tumors. Nevertheless, there have been no investigations of AOC1 and its regulatory mechanism in prostate cancer. Here, we reveal a novel action of AOC1 and a tumor suppressor mechanism in prostate cancer. AOC1 is downregulated in prostate cancer. Abatement of AOC1 in prostate cancer tissue is positively correlated with the tumor size, lymph node metastasis, and Gleason score for prostate cancer. Conversely, high expression of AOC1 is significantly associated with reduced proliferation and migration in prostate cancer both in vitro and in vivo. We show that the anticancer effect of AOC1 is mediated by its action on spermidine which leads to the activation of reactive oxygen species and ferroptosis. AOC1 expression in prostate cancer is positively regulated by the transcription factor SOX15. Therefore, SOX15 can transcriptionally promote AOC1 expression and strengthen this effect. Targeting AOC1 and SOX15 may be promising for the treatment of prostate cancer.
    DOI:  https://doi.org/10.1038/s41419-022-05108-w
  3. Theranostics. 2022 ;12(12): 5258-5271
    DCLK1 promotes colorectal cancer stemness and aggressiveness via the XRCC5/COX2 axis.
    Jee-Heun Kim, So-Yeon Park, So-El Jeon, Jang-Hyun Choi, Choong-Jae Lee, Tae-Young Jang, Hyeon-Ji Yun, Yuno Lee, Pilho Kim, Sang Hee Cho, Ji Shin Lee, Jeong-Seok Nam.
      Rationale: Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase that selectively marks cancer stem-like cells (CSCs) and promotes malignant progression in colorectal cancer (CRC). However, the exact molecular mechanism by which DCLK1 drives the aggressive phenotype of cancer cells is incompletely determined. Methods: Here, we performed comprehensive genomics and proteomics analyses to identify binding proteins of DCLK1 and discovered X-ray repair cross-complementing 5 (XRCC5). Thus, we explored the biological role and downstream events of the DCLK1/XRCC5 axis in human CRC cells and CRC mouse models. Results: The results of comprehensive bioinformatics analyses suggested that DCLK1-driven CRC aggressiveness is linked to inflammation. Mechanistically, DCLK1 bound and phosphorylated XRCC5, which in turn transcriptionally activated cyclooxygenase-2 expression and enhanced prostaglandin E2 production; these events collectively generated the inflammatory tumor microenvironment and enhanced the aggressive behavior of CRC cells. Consistent with the discovered mechanism, inhibition of DCLK1 kinase activity strongly impaired the tumor seeding and growth capabilities in CRC mouse models. Conclusion: Our study illuminates a novel mechanism that mediates the pro-inflammatory function of CSCs in driving the aggressive phenotype of CRC, broadening the biological function of DCLK1 in CRC.
    Keywords:  Cancer stem cells; Doublecortin-like kinase 1; Inflammatory tumor microenvironment; Prostaglandin E2
    DOI:  https://doi.org/10.7150/thno.72037
  4. Sci Adv. 2022 Aug 05. 8(31): eabn3986
    A SOX2-engineered epigenetic silencer factor represses the glioblastoma genetic program and restrains tumor development.
    Valerio Benedetti, Federica Banfi, Mattia Zaghi, Raquel Moll-Diaz, Luca Massimino, Laura Argelich, Edoardo Bellini, Simone Bido, Sharon Muggeo, Gabriele Ordazzo, Giuseppina Mastrototaro, Matteo Moneta, Alessandro Sessa, Vania Broccoli.
      Current therapies remain unsatisfactory in preventing the recurrence of glioblastoma multiforme (GBM), which leads to poor patient survival. By rational engineering of the transcription factor SOX2, a key promoter of GBM malignancy, together with the Kruppel-associated box and DNA methyltransferase3A/L catalytic domains, we generated a synthetic repressor named SOX2 epigenetic silencer (SES), which induces the transcriptional silencing of its original targets. By doing so, SES kills both glioma cell lines and patient-derived cancer stem cells in vitro and in vivo. SES expression, through local viral delivery in mouse xenografts, induces strong regression of human tumors and survival rescue. Conversely, SES is not harmful to neurons and glia, also thanks to a minimal promoter that restricts its expression in mitotically active cells, rarely present in the brain parenchyma. Collectively, SES produces a significant silencing of a large fraction of the SOX2 transcriptional network, achieving high levels of efficacy in repressing aggressive brain tumors.
    DOI:  https://doi.org/10.1126/sciadv.abn3986
  5. Sci Rep. 2022 Jul 30. 12(1): 13135
    Ym155 localizes to the mitochondria leading to mitochondria dysfunction and activation of AMPK that inhibits BMP signaling in lung cancer cells.
    Arindam Mondal, Dongxuan Jia, Vrushank Bhatt, Moumen Akel, Jacques Roberge, Jessie Yanxiang Guo, John Langenfeld.
      The imidazolium compound Ym155 was first reported to be a survivin inhibitor. Ym155 potently induces cell death of many types of cancer cells in preclinical studies. However, in phase II clinical trials Ym155 failed to demonstrate a significant benefit. Studies have suggested that the cytotoxic effects of Ym155 in cancer cells are not mediated by the inhibition of survivin. Understanding the mechanism by which Ym155 induces cell death would provide important insight how to improve its efficacy as a cancer therapeutic. We demonstrate a novel mechanism by which Ym155 induces cell death by localizing to the mitochondria causing mitochondrial dysfunction. Our studies suggest that Ym155 binds mitochondrial DNA leading to a decrease in oxidative phosphorylation, decrease in TCA cycle intermediates, and an increase in mitochondrial permeability. Furthermore, we show that mitochondrial stress induced by Ym155 and other mitochondrial inhibitors activates AMP-activated kinase leading to the downregulation to bone morphogenetic protein (BMP) signaling. We provide first evidence that Ym155 initiates cell death by disrupting mitochondrial function.
    DOI:  https://doi.org/10.1038/s41598-022-17446-y
  6. Nat Commun. 2022 Aug 05. 13(1): 4554
    Metabolic reprogramming from glycolysis to fatty acid uptake and beta-oxidation in platinum-resistant cancer cells.
    Yuying Tan, Junjie Li, Guangyuan Zhao, Kai-Chih Huang, Horacio Cardenas, Yinu Wang, Daniela Matei, Ji-Xin Cheng.
      Increased glycolysis is considered as a hallmark of cancer. Yet, cancer cell metabolic reprograming during therapeutic resistance development is under-studied. Here, through high-throughput stimulated Raman scattering imaging and single cell analysis, we find that cisplatin-resistant cells exhibit increased fatty acids (FA) uptake, accompanied by decreased glucose uptake and lipogenesis, indicating reprogramming from glucose to FA dependent anabolic and energy metabolism. A metabolic index incorporating glucose derived anabolism and FA uptake correlates linearly to the level of cisplatin resistance in ovarian cancer (OC) cell lines and primary cells. The increased FA uptake facilitates cancer cell survival under cisplatin-induced oxidative stress by enhancing beta-oxidation. Consequently, blocking beta-oxidation by a small molecule inhibitor combined with cisplatin or carboplatin synergistically suppresses OC proliferation in vitro and growth of patient-derived xenografts in vivo. Collectively, these findings support a rapid detection method of cisplatin-resistance at single cell level and a strategy for treating cisplatin-resistant tumors.
    DOI:  https://doi.org/10.1038/s41467-022-32101-w
  7. Front Oncol. 2022 ;12 952371
    Targeting SREBP-1-Mediated Lipogenesis as Potential Strategies for Cancer.
    Qiushi Zhao, Xingyu Lin, Guan Wang.
      Sterol regulatory element binding protein-1 (SREBP-1), a transcription factor with a basic helix-loop-helix leucine zipper, has two isoforms, SREBP-1a and SREBP-1c, derived from the same gene for regulating the genes of lipogenesis, including acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase. Importantly, SREBP-1 participates in metabolic reprogramming of various cancers and has been a biomarker for the prognosis or drug efficacy for the patients with cancer. In this review, we first introduced the structure, activation, and key upstream signaling pathway of SREBP-1. Then, the potential targets and molecular mechanisms of SREBP-1-regulated lipogenesis in various types of cancer, such as colorectal, prostate, breast, and hepatocellular cancer, were summarized. We also discussed potential therapies targeting the SREBP-1-regulated pathway by small molecules, natural products, or the extracts of herbs against tumor progression. This review could provide new insights in understanding advanced findings about SREBP-1-mediated lipogenesis in cancer and its potential as a target for cancer therapeutics.
    Keywords:  SREBP-1; cancer therapy; fatty acid synthase; fatty acids; lipogenesis
    DOI:  https://doi.org/10.3389/fonc.2022.952371
  8. Trends Cancer. 2022 Jul 28. pii: S2405-8033(22)00156-X. [Epub ahead of print]
    Emerging metabolomic tools to study cancer metastasis.
    Luiza Martins Nascentes Melo, Nicholas P Lesner, Marie Sabatier, Jessalyn M Ubellacker, Alpaslan Tasdogan.
      Metastasis is responsible for 90% of deaths in patients with cancer. Understanding the role of metabolism during metastasis has been limited by the development of robust and sensitive technologies that capture metabolic processes in metastasizing cancer cells. We discuss the current technologies available to study (i) metabolism in primary and metastatic cancer cells and (ii) metabolic interactions between cancer cells and the tumor microenvironment (TME) at different stages of the metastatic cascade. We identify advantages and disadvantages of each method and discuss how these tools and technologies will further improve our understanding of metastasis. Studies investigating the complex metabolic rewiring of different cells using state-of-the-art metabolomic technologies have the potential to reveal novel biological processes and therapeutic interventions for human cancers.
    Keywords:  analytical techniques; cancer metabolism; cancer metastasis; metabolomics
    DOI:  https://doi.org/10.1016/j.trecan.2022.07.003
  9. Neoplasia. 2022 Jul 29. pii: S1476-5586(22)00051-3. [Epub ahead of print]32 100824
    Metabolic reprogramming by adenosine antagonism and implications in non-small cell lung cancer therapy.
    Shuxiao Guan, Shankar Suman, Joseph M Amann, Ruohan Wu, David P Carbone, Jie Wang, Mikhail M Dikov.
      Non-small cell lung cancer (NSCLC) is a heterogeneous disease with genetic and environmental parameters that influence cell metabolism. Because of the complex interplay of environmental factors within the tumor microenvironment (TME) and the profound impact of these factors on the metabolic activities of tumor and immune cells, there is an emerging interest to advance the understanding of these diverse metabolic phenotypes in the TME. High levels of adenosine are characteristic of the TME, and adenosine can have a significant impact on both tumor cell growth and the immune response. Consistent with this, we showed in NSCLC data from TCGA that high expression of the A2BR leads to worse outcome and that expression of A2BR may be different for different mutation backgrounds. We then investigated the metabolic reprogramming of tumor cells and immune cells (T and dendritic cells) by adenosine. We used A2AR and A2BR antagonism or agonism as well as receptor knockout animals to explore whether these treatments altered specific immune compartments or conferred specific therapeutic vulnerabilities. Using the seahorse assay, we found that an A2BR antagonist modulates oxidative stress homeostasis in NSCLC cell lines. In addition, we found distinct metabolic roles of A2AR and A2BR receptors in T cell activation and dendritic cell maturation. These data suggest potential mechanisms and therapeutic benefits of A2 receptor antagonist therapy in NSCLC.
    Keywords:  A2AR/A2BR antagonist; Gene mutation; Metabolism; Non-small cell lung cancer; Tumor and immune cells; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.neo.2022.100824
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