Acquired platinum resistance involves epithelial to mesenchymal transition through ubiquitin ligase FBXO32 dysregulation

Tanaka, Nobuyuki; Kosaka, Takeo; Miyazaki, Yasumasa; Mikami, Shuji; Niwa, Naoya; Otsuka, Yutaro; Minamishima, Yoji Andrew; Mizuno, Ryuichi; Kikuchi, Eiji; Miyajima, Akira; Sabe, Hisataka; Okada, Yasunori; Uhlén, Per; Suematsu, Makoto; Oya, Mototsugu

doi:10.1172/jci.insight.83654

Cited by 25 publications

(24 citation statements)

References 46 publications

(63 reference statements)

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“…462 The molecular mechanisms of anti-cancer drug resistance are also associated with tumor metabolism, the TME and CSCs, such as increasing drug metabolism and degradation of drug target proteins, enhance the tolerability of stressful TME conditions, and enhance the DNA damage response and antiapoptotic mechanisms of CSCs. 461,[463][464][465][466] Thus, to improve therapeutic effects, a multitargeted combination treatment is proposed for UPS inhibitors.…”

Section: Targeting E3 Enzymesmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

415

308

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Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.Signal Transduction and Targeted Therapy (2020) 5:11; https://doi.

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Section: Targeting E3 Enzymesmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

415

308

View full text Add to dashboard Cite

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“…FBXO32 is also well recognized since its upregulation during skeletal muscle atrophy (102), which is known to negatively regulate epithelial to mesenchymal transition in platinum resistant-urothelial carcinoma cells (103). Furthermore, FBXO32 enhances chemosensitivity to cisplatin by inducing apoptosis in ovarian cancer cells (104).…”

Section: Other F-box Proteins Involved In Chemoresistancementioning

confidence: 99%

F‑box proteins involved in cancer‑associated drug resistance (Review)

et al. 2018

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The ubiquitin proteasome system (UPS) regulated human biological processes through the appropriate and efficient proteolysis of cellular proteins. F-box proteins are the vital components of SKP1-CUL1-FBP (SCF)-type E3 ubiquitin ligases that determine substrate specificity. As F-box proteins have the ability to control the degradation of several crucial protein targets associated with drug resistance, the dysregulation of these proteins may lead to induction of chemoresistance in cancer cells. Chemotherapy is one of the most conventional therapeutic approaches of treatment of patients with cancer. However, its exclusive application in clinical settings is restricted due to the development of chemoresistance, which typically results treatment failure. Therefore, overcoming drug resistance is considered as one of the most critical issues that researchers and clinician associated with oncology face. The present review serves to provide a comprehensive overview of F-box proteins and their possible targets as well as their correlation with the chemoresistance and chemosensitization of cancer cells. The article also presents an integrated representation of the complex regulatory mechanisms responsible for chemoresistance, which may lay the foundation to explore sensible candidate drugs for therapeutic intervention.

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“…First, we designed a workflow to detect transcriptome differences between urinary bladder cancer cells that were responsive (5637) or resistant (5637PR) to platinum treatment, applying Fluidigm C1 scRNA‐seq (Figure A). The 5637PR subpopulation were derived from 5637 cells and had acquired platinum‐resistance . By treating these cells with either CDDP or vehicle before sequencing we designed a model with four cell libraries: 5637 (n = 62), stressed 5637 (n = 63), 5637PR (n = 65), and stressed 5637PR (n = 59), which were prepared by single‐cell tagged reverse transcription (STRT) .…”

Section: Resultsmentioning

confidence: 99%

“…Urinary urothelial cancer cell line 5637 was obtained from the American Type Culture Collection (ATCC) and was certified mycoplasma‐free. 5637PR cells were established in our laboratory as an acquired platinum‐resistant sub‐line of 5637 . Briefly, 5637 cells were passaged 1‐2 times per week in medium containing CDDP over a 6‐month period, with a gradual increase in CDDP concentration up to 3 μmol/L.…”

Section: Methodsmentioning

confidence: 99%

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Single‐cell RNA‐seq analysis reveals the platinum resistance gene COX7B and the surrogate marker CD63

et al. 2018

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Cancers acquire resistance to systemic treatment with platinum‐based chemotherapy (eg, cisplatin [CDDP]) as a result of a dynamic intratumoral heterogeneity (ITH) and clonal repopulation. However, little is known about the influence of chemotherapy on ITH at the single‐cell level. Here, mapping the transcriptome of cancers treated with CDDP by scRNA‐seq, we uncovered a novel gene, COX7B, associated with platinum‐resistance, and surrogate marker, CD63. Knockdown of COX7B in cancer cells decreased the sensitivity of CDDP whereas overexpression recovered the sensitivity of CDDP. Low COX7B levels correlated with higher mortality rates in patients with various types of cancer and were significantly associated with poor response to chemotherapy in urinary bladder cancer. Tumor samples from patients, who underwent CDDP therapy, showed decreased COX7B protein levels after the treatment. Analyzing scRNA‐seq data from platinum‐naïve cancer cells demonstrated a low‐COX7B subclone that could be sorted out from bulk cancer cells by assaying CD63. This low‐COX7B subclone behaved as cells with acquired platinum‐resistance when challenged to CDDP. Our results offer a new transcriptome landscape of platinum‐resistance that provides valuable insights into chemosensitivity and drug resistance in cancers, and we identify a novel platinum resistance gene, COX7B, and a surrogate marker, CD63.

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Acquired platinum resistance involves epithelial to mesenchymal transition through ubiquitin ligase FBXO32 dysregulation

Cited by 25 publications

References 46 publications

The role of ubiquitination in tumorigenesis and targeted drug discovery

The role of ubiquitination in tumorigenesis and targeted drug discovery

F‑box proteins involved in cancer‑associated drug resistance (Review)

Single‐cell RNA‐seq analysis reveals the platinum resistance gene COX7B and the surrogate marker CD63

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