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.
Highlights
A new paradigm shift in the field of cancer cell biology is being driven by the concept of a key cancer cell population controlling the whole tumor, termed “cancer stem cells (CSCs)” [1]
The key driving pathways of CSCs, such as the PI3K/AKT/mammalian target of rapamycin (mTOR) and JAK/signal transducer and activator of transcription 3 (STAT3) signals, were found to be significantly increased in cancers with high CSC properties, and investigations of many small molecules targeting such pathways are ongoing in clinical trials [6,7]
Treatment of human non-small cell lung cancer cells (NSCLCs) H460 with 10 to 20 μM of gigantol for 24 and 48 h had a nonsignificant effect on survival of the cells, while a significant reduction of cell survival could be first detected in response to gigantol at a concentration of 50 μM (Figure 1B)
Summary
A new paradigm shift in the field of cancer cell biology is being driven by the concept of a key cancer cell population controlling the whole tumor, termed “cancer stem cells (CSCs)” [1]. CSCs from various types of cancers share a number of conservation properties, such as self-renewal ability, the generation of multiple types of differentiated cancer cells to drive tumor growth and heterogeneity, and resistance to chemotherapy via an upsurge of the DNA repair system and drug efflux transporter [2]. The key driving pathways of CSCs, such as the PI3K/AKT/mTOR and JAK/STAT3 signals, were found to be significantly increased in cancers with high CSC properties, and investigations of many small molecules targeting such pathways are ongoing in clinical trials [6,7]. Protein kinase B (PKB) or AKT, which is, frequently upregulated in lung cancer plays a key role in cell survival and proliferation [8].
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