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Targeting TUBG1 in RB1-negative tumors

Lindström, Lisa LU ; Zhou, Jingkai LU ; Villoutreix, Bruno O ; Malycheva, Darina LU ; Otrocka, Magdalena ; Gustavsson, Anna-Lena ; Lundbäck, Thomas ; Bliman, David LU ; Shameem, Muhammad Anwar LU and Straw, Megan LU , et al. (2025) In FASEB journal : official publication of the Federation of American Societies for Experimental Biology 39(5).
Abstract

The disruption of microtubule dynamics serves as a pivotal strategy for eliminating tumor cells, despite its accompanying toxicities affecting non-tumor cells. This study investigates the potential of selectively targeting γ-tubulin1 (TUBG1) as a therapeutic strategy in cancer treatment. By elucidating the TUBG1-E2F1-retinoblastoma protein (RB1) network, we introduce a novel compound, 4-(6-((3-Methoxyphenyl)amino)pyrimidin-4-yl)-N,N-dimethylbenzenamine, (L12). L12 treatment enhanced RB1 expression and selectively targeted cells with impaired RB1 signaling, while reduced E2F1 expression attenuated its cytotoxicity. Furthermore, L12-mediated cytotoxicity depends on an E2F1-mediated upregulation of procaspase 3 expression, highlighting the... (More)

The disruption of microtubule dynamics serves as a pivotal strategy for eliminating tumor cells, despite its accompanying toxicities affecting non-tumor cells. This study investigates the potential of selectively targeting γ-tubulin1 (TUBG1) as a therapeutic strategy in cancer treatment. By elucidating the TUBG1-E2F1-retinoblastoma protein (RB1) network, we introduce a novel compound, 4-(6-((3-Methoxyphenyl)amino)pyrimidin-4-yl)-N,N-dimethylbenzenamine, (L12). L12 treatment enhanced RB1 expression and selectively targeted cells with impaired RB1 signaling, while reduced E2F1 expression attenuated its cytotoxicity. Furthermore, L12-mediated cytotoxicity depends on an E2F1-mediated upregulation of procaspase 3 expression, highlighting the role of E2F1 in the apoptotic response. Unlike traditional tubulin-targeting agents, L12's specificity for tumor cells lies in its inhibitory effects on TUBG1, without affecting the second human isoform of TUBGs, TUBG2. Despite its interaction with specific kinases, the concentrations required for antitumor effects are 100-fold lower than those influencing kinase activities. Subsequent investigations underscore L12's reduced neuronal axonal toxicity compared to vincristine. Lastly, L12 demonstrates promising results in inhibiting tumor growth in xenografted small cell lung cancer models, demonstrating potential specificity toward tumor cells while minimizing adverse effects on healthy tissues. This research emphasizes the potential of TUBG1 inhibitors as a promising advancement in personalized chemotherapy approaches and their potential as a groundbreaking treatment for various cancers.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Animals, Tubulin/metabolism, Mice, Cell Line, Tumor, Apoptosis/drug effects, Xenograft Model Antitumor Assays, Mice, Nude, Antineoplastic Agents/pharmacology, Retinoblastoma Protein/metabolism, Neoplasms/drug therapy, Cell Proliferation/drug effects, Ubiquitin-Protein Ligases, Retinoblastoma Binding Proteins
in
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
volume
39
issue
5
article number
e70431
publisher
Wiley
external identifiers
  • scopus:85219638014
  • pmid:40019206
ISSN
1530-6860
DOI
10.1096/fj.202403180RR
language
English
LU publication?
yes
id
0aedab52-db80-414a-a796-f24e1a37143c
date added to LUP
2025-03-03 08:47:37
date last changed
2025-07-15 11:09:30
@article{0aedab52-db80-414a-a796-f24e1a37143c,
  abstract     = {{<p>The disruption of microtubule dynamics serves as a pivotal strategy for eliminating tumor cells, despite its accompanying toxicities affecting non-tumor cells. This study investigates the potential of selectively targeting γ-tubulin1 (TUBG1) as a therapeutic strategy in cancer treatment. By elucidating the TUBG1-E2F1-retinoblastoma protein (RB1) network, we introduce a novel compound, 4-(6-((3-Methoxyphenyl)amino)pyrimidin-4-yl)-N,N-dimethylbenzenamine, (L12). L12 treatment enhanced RB1 expression and selectively targeted cells with impaired RB1 signaling, while reduced E2F1 expression attenuated its cytotoxicity. Furthermore, L12-mediated cytotoxicity depends on an E2F1-mediated upregulation of procaspase 3 expression, highlighting the role of E2F1 in the apoptotic response. Unlike traditional tubulin-targeting agents, L12's specificity for tumor cells lies in its inhibitory effects on TUBG1, without affecting the second human isoform of TUBGs, TUBG2. Despite its interaction with specific kinases, the concentrations required for antitumor effects are 100-fold lower than those influencing kinase activities. Subsequent investigations underscore L12's reduced neuronal axonal toxicity compared to vincristine. Lastly, L12 demonstrates promising results in inhibiting tumor growth in xenografted small cell lung cancer models, demonstrating potential specificity toward tumor cells while minimizing adverse effects on healthy tissues. This research emphasizes the potential of TUBG1 inhibitors as a promising advancement in personalized chemotherapy approaches and their potential as a groundbreaking treatment for various cancers.</p>}},
  author       = {{Lindström, Lisa and Zhou, Jingkai and Villoutreix, Bruno O and Malycheva, Darina and Otrocka, Magdalena and Gustavsson, Anna-Lena and Lundbäck, Thomas and Bliman, David and Shameem, Muhammad Anwar and Straw, Megan and Riesbeck, Kristian and Olsson, Roger and Alvarado-Kristensson, Maria}},
  issn         = {{1530-6860}},
  keywords     = {{Humans; Animals; Tubulin/metabolism; Mice; Cell Line, Tumor; Apoptosis/drug effects; Xenograft Model Antitumor Assays; Mice, Nude; Antineoplastic Agents/pharmacology; Retinoblastoma Protein/metabolism; Neoplasms/drug therapy; Cell Proliferation/drug effects; Ubiquitin-Protein Ligases; Retinoblastoma Binding Proteins}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{5}},
  publisher    = {{Wiley}},
  series       = {{FASEB journal : official publication of the Federation of American Societies for Experimental Biology}},
  title        = {{Targeting TUBG1 in RB1-negative tumors}},
  url          = {{http://dx.doi.org/10.1096/fj.202403180RR}},
  doi          = {{10.1096/fj.202403180RR}},
  volume       = {{39}},
  year         = {{2025}},
}