Gigantol Targets Cancer Stem Cells and Destabilizes Tumors via the Suppression of the PI3K/AKT and JAK/STAT Pathways in Ectopic Lung Cancer Xenografts

Abstract

Lung cancer has long been recognized as an important world heath concern due to its high incidence and death rate. The failure of treatment strategies, as well as the regrowth of the disease driven by cancer stem cells (CSCs) residing in the tumor, lead to the urgent need for a novel CSC-targeting therapy. Here, we utilized proteome alteration analysis and ectopic tumor xenografts to gain insight on how gigantol, a bibenzyl compound from orchid species, could attenuate CSCs and reduce tumor integrity. The proteomics revealed that gigantol affected several functional proteins influencing the properties of CSCs, especially cell proliferation and survival. Importantly, the PI3K/AKT/mTOR and JAK/STAT related pathways were found to be suppressed by gigantol, while the JNK signal was enhanced. The in vivo nude mice model confirmed that pretreatment of the cells with gigantol prior to a tumor becoming established could decrease the cell division and tumor maintenance. The results indicated that gigantol decreased the relative tumor weight with dramatically reduced tumor cell proliferation, as indicated by Ki-67 labeling. Although gigantol only slightly altered the epithelial-to-mesenchymal and angiogenesis statuses, the gigantol-treated group showed a dramatic loss of tumor integrity as compared with the well-grown tumor mass of the untreated control. This study reveals the effects of gigantol on tumor initiation, growth, and maintain in the scope that the cells at the first step of tumor initiation have lesser CSC property than the control untreated cells. This study reveals novel insights into the anti-tumor mechanisms of gigantol focused on CSC targeting and destabilizing tumor integrity via suppression of the PI3K/AKT/mTOR and JAK/STAT pathways. This data supports the potential of gigantol to be further developed as a drug for lung cancer.

Analysis of the infant gut microbiome reveals metabolic functional roles associated with healthy infants and infants with atopic dermatitis using metaproteomics

“…The stool samples were collected from 9-12 months of age and frozen at −80 • C until analysis. Sample preparation was conducted as previously described by Losuwannarak et al (2019)). Briefly, frozen fecal samples were reconstituted in 50 mM phosphate buffer pH 7.0 and then vortexed well.…”

Gigantol Targets MYC for Ubiquitin-proteasomal Degradation and Suppresses Lung Cancer Cell Growth

“…Several effects of gigantol on aggressive phenotypes of lung cancer have been studied. Previous studies showed that gigantol suppressed EMT, migration and invasion, stem cell-like phenotype, and tumorigenicity (13,14,17). As far as we are aware, the antiproliferative effect of gigantol has not been explored.…”

“…Gigantol has been reported to have anticancer properties against several cancer types including breast, liver, and lung cancer, while having a low toxic effect on normal cells (12,(15)(16)(17). Several effects of gigantol on aggressive phenotypes of lung cancer have been studied.…”

“…MYC is also positively regulated by AKT via AKT-mediated GSK3β inactivation (11). Previous studies demonstrated that gigantol inhibited AKT function by reducing an active form of AKT (phosphorylated AKT at Ser473) in lung cancer (14,17), therefore it was possible that gigantol might enhance GSK3β function. Nevertheless, an effect of gigantol on GSK3β was unclear.…”

Role of Natural Bioactive Compounds in the Rise and Fall of Cancers

“…pathway, GLUT-1, PKM2 and MCT4, likely resulting in a decreased glucose entrance and biomass production [5]; -Oleacein (3,4-dihydroxyphenylethanol), the main secoiridoid contained in extra virgin olive oil, able to elicit significant anti-tumor activity by promoting cell cycle arrest and apoptosis in multiple myeloma cells due to its histone deacetylase inhibitory properties [6]; -Dadzein (7,4 -dihydroxyisoflavone), present in soybeans, whose 4-sulphate metabolite produced by gut microbiota was found to exert an anti-estrogenic effect on ERα-positive breast cancer cells via the downregulation of the anti-apoptotic neuroglobin protein thus rendering cells more prone to the paclitaxel treatment [7]; -Gigantol, a bibenzyl compound from orchid species, whose ability to destabilize tumor integrity via the suppression of the PI3K/AKT/mTOR and JAK/STAT pathways was demonstrated by Losuwannarak et al [8] in non-small-cell lung cancer models in vitro and in vivo; -Lonchocarpin, a chalcone isolated from Lonchocarpus sericeus, proven to be a powerful inhibitor of the Wnt/β-catenin pathway able to selectively suppress the migration and proliferation of a panel of colorectal cancer cell lines in vitro and in a preclinical colorectal cancer mouse model [9]; -Isorhamnetin, (3 -methoxy-3,4 ,5,7-tetrahydroxyflavone), a flavonol aglycone found in some medicinal plants, able to exert an anti-proliferative effect on human bladder cancer cells via the induction of cell cycle arrest during the G2/M phase and apoptosis, accompanied by the activation of the AMPK signaling pathway and ROS overproduction [10]; -Erioquinol, eriopodol A and gibbilimbol B, derived from Piper genus plants, whose ability to inhibit XIAP protein, involved in the regulation of caspase-dependent/independent cell death pathways, was reported by Muñoz et al [11] in breast cancer cell lines; -Vatein, isolated from Calocedrus formosana Florin leaves extract, proven to interfere with cell cycle and microtubule dynamics in lung adenocarcinoma cells, also inhibiting tumor growth in a xenograft mouse model [12].…”