Alantolactone is a natural product that potently inhibits YAP1/TAZ through promotion of reactive oxygen species accumulation

Abstract

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Alantolactone: A Natural Plant Extract as a Potential Therapeutic Agent for Cancer

“…For example, mitogen-activated protein kinases (p38 MAPK) and NF-κB signaling pathways are significantly attenuated by ALT, inhibiting cell viability and promoting cell apoptosis in lung cancer cell lines NCI-H1299 and Anip973 (Liu et al, 2019). And a recent study firstly reported that ALT could suppress the activation of YAP1/TAZ, leading to the inhibition of cancer cell growth (Nakatani et al, 2021). ALT could downregulate the serine/threonine kinase Aurora-A through directly binding to the interface pocket of Aurora-A-TPX2 complex, weakening several cancerassociated biological behaviors, including centrosome amplification, chromosomal instability and oncogenic transformations (Bhardwaj and Purohit, 2020;Nadda et al, 2020).…”

N‐(3,4‐dimethoxyphenethyl)‐6‐methyl‐2,3,4,9‐tetrahydro‐1H‐carbazol‐1‐amine inhibits bladder cancer progression by suppressing YAP1/TAZ

“…To this end, we screened a library of 29,049 low‐molecular‐weight chemical compounds using our previously described YAP1/TAZ‐TEAD reporter system (Nakatani et al, 2021; Nishio et al, 2016). As judged by: (1) inhibition of reporter activity (more than 50% decrease); (2) reduction in YAP1 protein levels (more than a 75% decrease); and (3) suppressed expression of YAP1 downstream target genes, we found nine compounds (out of 29,049) to be suitable candidates (Nakatani et al, 2021). Among these, four compounds (including the most potent agent) were alantolactone‐related molecules (Nakatani et al, 2021).…”

“…Importantly, in vivo administration of DMPCA markedly shrank the growth of T24 tumors in xenografted mice. (Nakatani et al, 2021). For the induction of Yap1 and Taz gene deletion in cultured iYap1/Taz DKO MEFs, cells were treated with 1 μM 4-hydroxytamoxifen (Tmx) for 7 days.…”

“…"Yesassociated protein-1" (YAP1) and "Transcriptional coactivator with PDZ-binding motif" (TAZ) are paralogous co-activators of the TEAD family of transcription factors, and so help to positively regulate many target genes involved in cell proliferation. Negative regulation of YAP1/TAZ is mediated by Hippo pathway elements, and activation of Hippo signaling is triggered by changes to cell polarity, cell-to-cell contact, soluble factors activating GPCRs or RTKs, integrins, matrix proteins, ECM stiffness, and/or reactive oxygen species (Ghasemi et al, 2020;Nakatani et al, 2017Nakatani et al, , 2021. The Hippo core consists of a cascade involving two types of kinases: the upstream "STE20-like protein" (MST) kinases and the downstream "Large tumor suppressor homolog" (LATS) kinases.…”

Yes-associated protein 1 exerts its tumor-promoting effects and increases cisplatin resistance in tongue squamous cell carcinoma cells by dysregulating Hippo signal pathway

“…Yes-associated protein 1 (YAP1) is one of the most key effectors of Hippo pathway. Generally, the upstream kinases of Hippo pathway form a complex and phosphorylate large tumor suppressor gene (LATS1/2), then the activated LATS1/2 kinase will phosphorylate YAP1 to inactivate it and also inhibit the transcriptional activity of YAP1 [13]. When the Hippo pathway is disordered, nonphosphorylated YAP1 will enter the nucleus and activate the transcription of proliferation-related molecules [14].…”