Jorunnamycin A from Xestospongia sp. Suppresses Epithelial to Mesenchymal Transition and Sensitizes Anoikis in Human Lung Cancer Cells

Abstract

Metastasis is a key driving force behind the high mortality rate associated with lung cancer. Herein, we report the first study revealing the antimetastasis activity of jorunnamycin A, a bistetrahydroisoquinoline­quinone isolated from a Thai blue sponge Xestospongia sp. evidenced by its inhibition of epithelial to mesenchymal transition (EMT), sensitization of anoikis, and suppression of anchorage-independent survival in human lung cancer cells. Treatment with jorunnamycin A (0.05–0.5 μM) altered the expression of p53 and Bcl-2 family proteins, particularly causing the down-regulation of antiapoptosis Bcl-2 and Mcl-1 proteins. Under detachment conditions for 12 h, jorunnamycin A-treated cells exhibited diminution of pro-survival proteins p-Akt and p-Erk as well as the survival-promoting factor caveolin-1. Corresponding with the inhibition on the Akt and Erk pathway as well as activation of p53, there was an increase in the epithelial marker E-cadherin and a remarkable decrease of EMT markers and associated proteins including vimentin, snail, and claudin-1. As the loss of anchorage dependence is an important barrier to metastasis, the observed inhibitory effects of jorunnamycin A on the coordinating networks of EMT and anchorage-independent growth emphasize the potential development of jorunnamycin A as an effective agent against lung cancer metastasis.

Multifaceted Roles of Caveolin-1 in Lung Cancer: A New Investigation Focused on Tumor Occurrence, Development and Therapy

“…In the nucleus, Foxo3a can increase the expression of Bax and caspase-3, then the cells exhibit reinforced apoptosis [151]. Jorunnamycin A is an extract from Xestospongia sp., which can suppress Cav-1 expression to inhibit EMT and survival in H460, H292 and H23 cells [152]. By decreasing Cav-1 expression, EEAC can make A549 cells more sensitive to paclitaxel treatment and slow down cell viability [153].…”

Jorunnamycin A Suppresses Stem-Like Phenotypes and Sensitizes Cisplatin-Induced Apoptosis in Cancer Stem-Like Cell-Enriched Spheroids of Human Lung Cancer Cells

“…The downregulation of stemness transcription factors is mediated through the Akt/GSK-3β/β-catenin cascade [ 24 ], which correlates with the suppressive effect of jorunnamycin A on these key proteins in the CSC-enriched spheroids obtained from H460 cells ( Figure 3 D). Although jorunnamycin A-mediated downregulation of Akt signaling has been previously reported in various human lung cancer cells [ 35 ], the investigation of CSC-related mechanisms demonstrated the suppression of p-Akt/Akt level only in CSC-enriched H460 spheroids but not in CSC subpopulations derived from H23 ( Figure 6 C,D) and A549 cells ( Figure 6 E,F). The low correlation between Akt signal and down-stream molecules presented in H23 and A549 spheroids might result from the fact that the alteration of an up-stream mediator should be detected at an earlier time point.…”

“…According to the cytotoxic profile obtained from a previous study [ 35 ], jorunnamycin A at a nontoxic concentration range between 0.05–0.5 μM was chosen for the evaluation of its targeting effect against the human lung CSC subpopulation. Herein, the half-maximal concentration that reduced 50% cell viability (IC 50 ) and inhibited 50% growth (IG 50 ) of jorunnamycin A in both lung cancer (H460, H23, and A549) and bronchial epithelial cells (BEAS-2B) was also determined and is presented in Table 1 .…”

“…A recent study revealed the inhibitory effect of renieramycin M on CSC features of lung cancer cells; however, its regulatory mechanism has never been investigated [ 34 ]. Interestingly, jorunnamycin A was found to promote detachment-induced cell death and to inhibit epithelial-to-mesenchymal transition (EMT) and anchorage-independent growth in human lung cancers [ 35 ]. This study aimed to investigate the suppressive activity of jorunnamycin A on stem-like phenotypes of CSCs from human lung cancer cells and its underlying mechanisms.…”

Collective Locomotion of Human Cells, Wound Healing and Their Control by Extracts and Isolated Compounds from Marine Invertebrates

“…(Demospongiae, Haplosclerida: Petrosiidae; Figure 7 is widely distributed in the Indian and South Pacific Oceans. These animals represent a rich source of secondary metabolites with very different biological properties that have been shown effective as enzymatic inhibitors, anti-malarial, anti-bacterial, vasodilatory, and anti-cancer agents [65][66][67][68][69][70]. Among them, ranieramycins are a group of biologically-active tetrahydroisoquinoline compounds.…”