bims-cadres Biomed News
on Cancer drug resistance
Issue of 2022‒07‒24
six papers selected by
Rana Gbyli
Yale University
  1. Cell Adhesion Signaling Regulates Cancer Stem Cell Dormancy after Chemotherapy.
  2. PI3K/Akt/mTOR signaling pathway in cancer stem cells.
  3. EZH2 regulates a SETDB1/ΔNp63α axis via RUNX3 to drive a cancer stem cell phenotype in squamous cell carcinoma.
  4. KS10076, a chelator for redox-active metal ions, induces ROS-mediated STAT3 degradation in autophagic cell death and eliminates ALDH1+ stem cells.
  5. Recent advances in the molecular basis of chemotherapy resistance and potential application of epigenetic therapeutics in chemorefractory renal cell carcinoma.
  6. Loss of EMP1 promotes the metastasis of human bladder cancer cells by promoting migration and conferring resistance to ferroptosis through activation of PPAR gamma signaling.
  1. Cancer Discov. 2022 Jul 22. OF1
    Cell Adhesion Signaling Regulates Cancer Stem Cell Dormancy after Chemotherapy.
      A 4D live imaging system identified LGR5+ p27+ cancer stem cells that persist after chemotherapy and contribute to disease relapse.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-129
  2. Pathol Res Pract. 2022 Jul 03. pii: S0344-0338(22)00254-0. [Epub ahead of print]237 154010
    PI3K/Akt/mTOR signaling pathway in cancer stem cells.
    Mohsen Karami Fath, Menooa Ebrahimi, Ehsan Nourbakhsh, Ahmad Zia Hazara, Ali Mirzaei, Saba Shafieyari, Azadeh Salehi, Mahsa Hoseinzadeh, Zahra Payandeh, Ghasem Barati.
      Cancer stem cells (CSCs) as a small subpopulation in tumor bulk are believed to initiate tumor formation and are responsible for the resistance to cancer therapy. The proliferation and differentiation of CSCs result in heterogeneity in a tumor which increases the chance of tumor survival and invasion. Many signaling pathways are abnormally activated or repressed in CSCs. Understanding these pathways and the metabolisms in CSCs may help targeted therapy in drug-resistant tumors. The PI3K/Akt/mTOR pathway is one of the major signaling pathways in CSCs involved in the maintenance of stemness, proliferation, differentiation, epithelial to mesenchymal transition (EMT), migration, and autophagy. Thus, suppressing the PI3K/Akt/mTOR pathway with inhibitors might be a promising strategy for targeted cancer therapy. Although the pathway is well-recognized and reviewed in tumor bulks, the functions in CSCs have not been well focused. Here, we reviewed the PI3K/Akt/mTOR signaling pathway and its functions in CSCs and addressed the potential therapeutic applications in drug-resistant tumors.
    Keywords:  Cancer stem cell; PI3K/Akt/mTOR pathway; Pathogenesis; Targeted cancer therapy
    DOI:  https://doi.org/10.1016/j.prp.2022.154010
  3. Oncogene. 2022 Jul 21.
    EZH2 regulates a SETDB1/ΔNp63α axis via RUNX3 to drive a cancer stem cell phenotype in squamous cell carcinoma.
    Seamus Balinth, Matthew L Fisher, Yon Hwangbo, Caizhi Wu, Carlos Ballon, Xueqin Sun, Alea A Mills.
      Enhancer of zeste homolog 2 (EZH2) and SET domain bifurcated 1 (SETDB1, also known as ESET) are oncogenic methyltransferases implicated in a number of human cancers. These enzymes typically function as epigenetic repressors of target genes by methylating histone H3 K27 and H3-K9 residues, respectively. Here, we show that EZH2 and SETDB1 are essential to proliferation in 3 SCC cell lines, HSC-5, FaDu, and Cal33. Additionally, we find both of these proteins highly expressed in an aggressive stem-like SCC sub-population. Depletion of either EZH2 or SETDB1 disrupts these stem-like cells and their associated phenotypes of spheroid formation, invasion, and tumor growth. We show that SETDB1 regulates this SCC stem cell phenotype through cooperation with ΔNp63α, an oncogenic isoform of the p53-related transcription factor p63. Furthermore, EZH2 is upstream of both SETDB1 and ΔNp63α, activating these targets via repression of the tumor suppressor RUNX3. We show that targeting this pathway with inhibitors of EZH2 results in activation of RUNX3 and repression of both SETDB1 and ΔNp63α, antagonizing the SCC cancer stem cell phenotype. This work highlights a novel pathway that drives an aggressive cancer stem cell phenotype and demonstrates a means of pharmacological intervention.
    DOI:  https://doi.org/10.1038/s41388-022-02417-4
  4. Cell Rep. 2022 Jul 19. pii: S2211-1247(22)00875-0. [Epub ahead of print]40(3): 111077
    KS10076, a chelator for redox-active metal ions, induces ROS-mediated STAT3 degradation in autophagic cell death and eliminates ALDH1+ stem cells.
    Jaehee Kim, Areum Park, Jieon Hwang, Xianghua Zhao, Jaesung Kwak, Hyun Woo Kim, Minhee Ku, Jaemoon Yang, Tae Il Kim, Kyu-Sung Jeong, Uyeong Choi, Hyuk Lee, Sang Joon Shin.
      Redox-active metal ions are pivotal for rapid metabolism, proliferation, and aggression across cancer types, and this presents metal chelation as an attractive cancer cell-targeting strategy. Here, we identify a metal chelator, KS10076, as a potent anti-cancer drug candidate. A metal-bound KS10076 complex with redox potential for generating hydrogen peroxide and superoxide anions induces intracellular reactive oxygen species (ROS). The elevation of ROS by KS10076 promotes the destabilization of signal transducer and activator of transcription 3, removes aldehyde dehydrogenase isoform 1-positive cancer stem cells, and subsequently induces autophagic cell death. Bioinformatic analysis of KS10076 susceptibility in pan-cancer cells shows that KS10076 potentially targets cancer cells with increased mitochondrial function. Furthermore, patient-derived organoid models demonstrate that KS10076 efficiently represses cancer cells with active KRAS, and fluorouracil resistance, which suggests clinical advantages.
    Keywords:  ALDH1+ stem cell elimination; CP: Cancer; ROS-induced STAT3 degradation; autophagic cell death; metal chelator; pan-cancer therapeutics
    DOI:  https://doi.org/10.1016/j.celrep.2022.111077
  5. WIREs Mech Dis. 2022 Jul 21. e1575
    Recent advances in the molecular basis of chemotherapy resistance and potential application of epigenetic therapeutics in chemorefractory renal cell carcinoma.
    Narayan Acharya, Kamaleshwar P Singh.
      Among various types of cancers, kidney cancer is unique with respect to a low frequency of mutations and a relatively higher level of chemotherapy resistance. Resistance to chemotherapy is a major challenge in kidney cancer treatment in the clinic. Tremendous progress has been made in identifying the molecular changes associated with chemotherapy resistance in RCC. However, the exact contribution of these molecular changes to the acquisition of chemotherapy resistance is not fully understood. In addition to genetic changes, epigenetic alterations have been shown to contribute to various pathways associated with chemotherapy resistance, such as increased cell proliferation and survival, regulation of drug influx and efflux transporters, increased DNA repair, loss of DNA-damage-dependent apoptotic potential, cellular dedifferentiation to cancer stem cell, and epithelial-mesenchymal transitions (EMT). Moreover, recent studies suggest that epigenetic aberrations that can be reversed by epigenetic therapeutics can potentially be targeted to restore chemosensitivity in chemorefractory kidney cancer. This review article highlights current knowledge of the role of genetic and epigenetic aberrations as well as the physiological and metabolic changes associated with chemotherapeutic resistance. Additionally, current approaches and future directions for overcoming chemotherapeutic resistance including the potential of epigenetic therapeutic in chemorefractory kidney cancer have also been discussed. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics.
    Keywords:  DNA methylation; chemotherapy resistance; epigenetics; renal cell carcinoma
    DOI:  https://doi.org/10.1002/wsbm.1575
  6. Free Radic Biol Med. 2022 Jul 16. pii: S0891-5849(22)00474-9. [Epub ahead of print]189 42-57
    Loss of EMP1 promotes the metastasis of human bladder cancer cells by promoting migration and conferring resistance to ferroptosis through activation of PPAR gamma signaling.
    Sha Liu, Jiazhong Shi, Liwei Wang, Yaqin Huang, Baixiong Zhao, Hua Ding, Yuting Liu, Wuxing Wang, Zhiwen Chen, Jin Yang.
      Metastasis, in which cancer cells detach from the original site and colonise other organs, is the primary cause of death induced by bladder cancer (BCa). Epithelial Membrane Protein 1 (EMP1) is dysregulated in many human cancers, and its clinical significance and biological function in diseases, including BCa, are largely unclear. Here, we demonstrated that EMP1 was downregulated in BCa cells. The deficiency of EMP1 promotes migration and confers resistance to ferroptosis/oxidative stress in BCa cells, favouring tumour cell metastasis. Mechanistically, we demonstrated that EMP1 deficiency enhanced tumour metastasis by increasing PPARG expression and promoting its activation, leading to upregulation of pFAK(Y397) and SLC7A11, which promoted cell migration and anti-ferroptotic cell death respectively. Moreover, we found EMP1-deficient sensitized cells to PPARG's ligand, which effect are metastatic phenotype promoted and could be mitigated by FABP4 knockdown. In conclusion, our study, for the first time, reveals that EMP1 deficiency promotes BCa cell migration and confers resistance to ferroptosis/oxidative stress, thus promoting metastasis of BCa via PPARG. These results revealed a novel role of EMP1-mediated PPARG in bladder cancer metastasis.
    Keywords:  Bladder cancer; EMP1; FABP4; Metastasis; PPAR-gamma (PPARG)
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.06.247
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