UBXN2A suppresses the Rictor-mTORC2 signaling pathway, an established tumorigenic pathway in human colorectal cancer

Sane, Sanam; Srinivasan, Rekha; Potts, Rashaun; Eikanger, Morgan; Zagirova, Diana; Freeling, Jessica; Reihe, Casey; Antony, Ryan; Gupta, Brij K.; Lynch, Douglas; Bleeker, Jonathan; Turaihi, Hassan; Pillatzki, Angela; Zhou, Wei; Luo, Xu; Linnebacher, Michael; Agany, Diing D.M.; Zohim, Etienne Gnimpieba; Humphrey, Lisa E.; Black, Adrian R.; Rezvani, Khosrow

doi:10.1038/s41388-023-02686-7

Cited by 3 publications

(2 citation statements)

References 87 publications

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“…Neogenin inhibits CRC progression and metastasis by binding to Merlin and subsequently enhances YAP phosphorylation [43]. UBXN2A inhibits CRC growth and metastasis by reducing AKT phosphorylation downstream of the dominant oncogenic pathway in CRC [44]. As for non-coding RNAs, linc00152 can block CK1-mediated cytoplasmic β-catenin phosphorylation and consequently facilitate β-catenin nuclear translocation, thus promoting colon cancer EMT and metastasis [45].…”

Section: Phosphorylation Regulates Emtmentioning

confidence: 99%

Role of Post-Translational Modifications in Colorectal Cancer Metastasis

Peng,

Liu,

Hai

et al. 2024

Cancers

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Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive tract. CRC metastasis is a multi-step process with various factors involved, including genetic and epigenetic regulations, which turn out to be a serious threat to CRC patients. Post-translational modifications (PTMs) of proteins involve the addition of chemical groups, sugars, or proteins to specific residues, which fine-tunes a protein’s stability, localization, or interactions to orchestrate complicated biological processes. An increasing number of recent studies suggest that dysregulation of PTMs, such as phosphorylation, ubiquitination, and glycosylation, play pivotal roles in the CRC metastasis cascade. Here, we summarized recent advances in the role of post-translational modifications in diverse aspects of CRC metastasis and its detailed molecular mechanisms. Moreover, advances in drugs targeting PTMs and their cooperation with other anti-cancer drugs, which might provide novel targets for CRC treatment and improve therapeutic efficacy, were also discussed.

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Section: Phosphorylation Regulates Emtmentioning

confidence: 99%

Role of Post-Translational Modifications in Colorectal Cancer Metastasis

Peng,

Liu,

Hai

et al. 2024

Cancers

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“…Recently, Sane et al. identified a new tumour suppressor in colorectal cancer called UBXN2A, capable of suppressing the mTORC2 signaling pathway via the ubiquitination of RICTOR for 26S proteasomal degradation, without effect on mTORC1 66 . These data highlight the importance of mTORC2 in colorectal cancer and the therapeutic potential of selective anti‐mTORC2 drugs for these tumours.…”

Section: Sin1 and Cancersmentioning

confidence: 99%

Unmasking the tumourigenic role of SIN1/MAPKAP1 in the mTOR complex 2

Ezine,

Lebbe,

Dumaz

2023

Clinical & Translational Med

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BackgroundAlthough the PI3K/AKT/mTOR pathway is one of the most altered pathways in human tumours, therapies targeting this pathway have shown numerous adverse effects due to positive feedback paradoxically activating upstream signaling nodes. The somewhat limited clinical efficacy of these inhibitors calls for the development of novel and more effective approaches for targeting the PI3K pathway for therapeutic benefit in cancer.Main bodyRecent studies have shown the central role of mTOR complex 2 (mTORC2) as a pro‐tumourigenic factor of the PI3K/AKT/mTOR pathway in a number of cancers. SIN1/MAPKAP1 is a major partner of mTORC2, acting as a scaffold and responsible for the substrate specificity of the mTOR catalytic subunit. Its overexpression promotes the proliferation, invasion and metastasis of certain cancers whereas its inhibition decreases tumour growth in vitro and in vivo. It is also involved in epithelial‐mesenchymal transition, stress response and lipogenesis. Moreover, the numerous interactions of SIN1 inside or outside mTORC2 connect it with other signaling pathways, which are often disrupted in human tumours such as Hippo, WNT, Notch and MAPK.ConclusionTherefore, SIN1's fundamental characteristics and numerous connexions with oncogenic pathways make it a particularly interesting therapeutic target. This review is an opportunity to highlight the tumourigenic role of SIN1 across many solid cancers and demonstrates the importance of targeting SIN1 with a specific therapy.

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RICTOR/mTORC2 downregulation in BRAFV600E melanoma cells promotes resistance to BRAF/MEK inhibition

Ponzone,

Audrito,

Landi

et al. 2024

Mol Cancer

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Background The main drawback of BRAF/MEK inhibitors (BRAF/MEKi)-based targeted therapy in the management of BRAF-mutated cutaneous metastatic melanoma (MM) is the development of therapeutic resistance. We aimed to assess in this context the role of mTORC2, a signaling complex defined by the presence of the essential RICTOR subunit, regarded as an oncogenic driver in several tumor types, including MM. Methods After analyzing The Cancer Genome Atlas MM patients’ database to explore both overall survival and molecular signatures as a function of intra-tumor RICTOR levels, we investigated the effects of RICTOR downregulation in BRAFV600E MM cell lines on their response to BRAF/MEKi. We performed proteomic screening to identify proteins modulated by changes in RICTOR expression, and Seahorse analysis to evaluate the effects of RICTOR depletion on mitochondrial respiration. The combination of BRAFi with drugs targeting proteins and processes emerged in the proteomic screening was carried out on RICTOR-deficient cells in vitro and in a xenograft setting in vivo. Results Low RICTOR levels in BRAF-mutated MM correlate with a worse clinical outcome. Gene Set Enrichment Analysis of low-RICTOR tumors display gene signatures suggestive of activation of the mitochondrial Electron Transport Chain (ETC) energy production. RICTOR-deficient BRAFV600E cells are intrinsically tolerant to BRAF/MEKi and anticipate the onset of resistance to BRAFi upon prolonged drug exposure. Moreover, in drug-naïve cells we observed a decline in RICTOR expression shortly after BRAFi exposure. In RICTOR-depleted cells, both mitochondrial respiration and expression of nicotinamide phosphoribosyltransferase (NAMPT) are enhanced, and their pharmacological inhibition restores sensitivity to BRAFi. Conclusions Our work unveils an unforeseen tumor-suppressing role for mTORC2 in the early adaptation phase of BRAFV600E melanoma cells to targeted therapy and identifies the NAMPT-ETC axis as a potential therapeutic vulnerability of low RICTOR tumors. Importantly, our findings indicate that the evaluation of intra-tumor RICTOR levels has a prognostic value in metastatic melanoma and may help to guide therapeutic strategies in a personalized manner.

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UBXN2A suppresses the Rictor-mTORC2 signaling pathway, an established tumorigenic pathway in human colorectal cancer

Cited by 3 publications

References 87 publications

Role of Post-Translational Modifications in Colorectal Cancer Metastasis

Role of Post-Translational Modifications in Colorectal Cancer Metastasis

Unmasking the tumourigenic role of SIN1/MAPKAP1 in the mTOR complex 2

RICTOR/mTORC2 downregulation in BRAFV600E melanoma cells promotes resistance to BRAF/MEK inhibition

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