AMPK-Fyn Signaling Promotes Notch1 Stability to Potentiate Hypoxia-Induced Breast&amp;nbsp;Cancer Stemness and Drug Resistance

Lahiry, Mohini; Kumar, Saurav; Hari, Kishore; Chedere, Adithya; Jolly, Mohit Kumar; Rangarajan, Annapoorni

doi:10.2139/ssrn.3586992

Cited by 6 publications

(2 citation statements)

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“…NOTCH and its interaction with ubiquitin ligases have often been shown to be influenced by regulators, such as NUMB, which suppresses NOTCH signaling by recruiting Itchy E3 ubiquitin-protein ligase (ITCH) and facilitating the degradation of NICD [37]. Under hypoxic conditions, AMPK impairs the interaction between NICD and ITCH via tyrosine kinase Fyn, thus stabilizing the cleaved NOTCH by reducing its ubiquitination and degradation in breast cancer cells [38]. Therefore, the PKA-AMPK axis may facilitate NOTCH degradation through NUMB/ITCH.…”

Section: Discussionmentioning

confidence: 99%

Mutant GNAS limits tumor aggressiveness in established pancreatic cancer via antagonizing the KRAS-pathway

et al. 2022

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Background Mutations in GNAS drive pancreatic tumorigenesis and frequently occur in intraductal papillary mucinous neoplasm (IPMN); however, their value as a therapeutic target is yet to be determined. This study aimed at evaluating the involvement of mutant GNAS in tumor aggressiveness in established pancreatic cancer. Methods CRISPR/Cas9-mediated GNAS R201H silencing was performed using human primary IPMN-associated pancreatic cancer cells. The role of oncogenic GNAS in tumor maintenance was evaluated by conducting cell culture and xenograft experiments, and western blotting and transcriptome analyses were performed to uncover GNAS-driven signatures. Results Xenografts of GNAS wild-type cells were characterized by a higher Ki-67 labeling index relative to GNASmutant cells. Phenotypic alterations in the GNAS wild-type tumors resulted in a significant reduction in mucin production accompanied by solid with massive stromal components. Transcriptional profiling suggested an apparent conflict of mutant GNAS with KRAS signaling. A significantly higher Notch intercellular domain (NICD) was observed in the nuclear fraction of GNAS wild-type cells. Meanwhile, inhibition of protein kinase A (PKA) induced NICD in GNAS-mutant IPMN cells, suggesting that NOTCH signaling is negatively regulated by the GNAS-PKA pathway. GNAS wild-type cells were characterized by a significant invasive property relative to GNAS-mutant cells, which was mediated through the NOTCH regulatory pathway. Conclusions Oncogenic GNAS induces mucin production, not only via MUC2 but also via MUC5AC/B, which may enlarge cystic lesions in the pancreas. The mutation may also limit tumor aggressiveness by attenuating NOTCH signaling; therefore, such tumor-suppressing effects must be considered when therapeutically inhibiting the GNAS pathway.

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Section: Discussionmentioning

confidence: 99%

Mutant GNAS limits tumor aggressiveness in established pancreatic cancer via antagonizing the KRAS-pathway

et al. 2022

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“…Previous studies have confirmed that the effect of lumiflavin is related to oxidative phosphorylation and oxidative stress ( 11 ). Moreover, Notch is closely related to stem cell signaling pathway, AMPK signaling pathway and cell cycle ( 31 , 52 , 53 ). Notch pathway is also critical for CSC differentiation and drug resistance in cancer ( 54 , 55 ).…”

Section: Discussionmentioning

confidence: 99%

Lumiflavin Reduces Cisplatin Resistance in Cancer Stem-Like Cells of OVCAR-3 Cell Line by Inducing Differentiation

et al. 2022

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Ovarian cancer stem-like cells (CSCs) play a vital role in drug resistance and recurrence of ovarian cancer. Inducing phenotypic differentiation is an important strategy to enhance the effects of chemotherapy and reduce the drug resistance of CSCs. This study found that lumiflavin, a riboflavin decomposition product, reduced the development of CSC resistance and enhanced the chemotherapy effect of cisplatin (DDP) on CSCs in DDP-resistant ovarian cancer OVCAR-3 cell line (CSCs/DDP) and was related to the induction of CSC phenotypic differentiation. Results showed that the development of DDP-resistant OVCAR-3 cells was related to the increase in the proportion of CSCs/DDP, and the treatment with lumiflavin reduced the DDP-resistance levels of OVCAR-3 cells and proportion of CSCs/DDP. Further investigation found that lumiflavin synergistic with DDP increased apoptosis, decreased mitochondrial membrane potential, and inhibited the clonal formation of CSCs/DDP. Meanwhile, in vivo experiments showed that lumiflavin dose-dependently enhanced the chemotherapy effect of DDP on tumor-bearing nude mice inoculated by CSCs/DDP. Lumiflavin treatment also reduced the ratio of CD133+/CD177+ to CD44+/CD24 cells, which is the identification of CSCs, in CSCs/DDP. In addition, transcriptome sequencing results suggested that the role of lumiflavin was related to the notch and stem cell pathway, and Western blot analysis showed that lumiflavin inhibited the protein expression of notch signaling pathway in CSCs/DDP. In conclusion, lumiflavin reduces the development of the drug resistance of OVCAR-3 cell and increases the sensitivity of CSCs/DDP to DDP by inducing phenotypic differentiation, which may have a potential role in the chemotherapy treatment of ovarian cancer.

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Lessons from the Embryo: an Unrejected Transplant and a Benign Tumor

Rezalotfi

Vrynas

Dehghanian

et al. 2020

Stem Cell Rev and Rep

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AMPK-Fyn Signaling Promotes Notch1 Stability to Potentiate Hypoxia-Induced Breast Cancer Stemness and Drug Resistance

Cited by 6 publications

References 0 publications

Mutant GNAS limits tumor aggressiveness in established pancreatic cancer via antagonizing the KRAS-pathway

Mutant GNAS limits tumor aggressiveness in established pancreatic cancer via antagonizing the KRAS-pathway

Lumiflavin Reduces Cisplatin Resistance in Cancer Stem-Like Cells of OVCAR-3 Cell Line by Inducing Differentiation

Lessons from the Embryo: an Unrejected Transplant and a Benign Tumor

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