Novel Lobophorins Inhibit Oral Cancer Cell Growth and Induce Atf4- and Chop-Dependent Cell Death in Murine Fibroblasts

Abstract

As part of the International Cooperative Biodiversity Groups (ICBG) Program, we were interested in identifying biologically active unfolded protein response (UPR) inducing compounds from marine microorganisms isolated from Costa Rican biota. With this aim in mind we have now generated more than 33,000 unique prefractionated natural product extracts from marine and terrestrial organisms that have been submitted to the Center of Chemical Genomics (CCG) at the University of Michigan for high throughput screening (HTS). An effective complementary cell-based assay to identify novel modulators of UPR signaling was used for screening extracts. Active fractions were iteratively subjected to reverse-phase HPLC chromatographic analysis, and together with lobophorin A, B, E, and F (1−4), three new lobophorin congeners, designated as CR1 (5), CR2 (6), and CR3 (7) were isolated. Herein, we report that secondary assays revealed that the new lobophorins induced UPR-associated gene expression, inhibited oral squamous cell carcinoma cell growth, and led to UPRdependent cell death in murine embryonic fibroblast (MEF) cells.

Marine natural products

“…and, subject to supply, further studies will examine the mechanism by which active lobophorins activate UPR. 51 The gene cluster for the anti-infective desotamides from S. scopuliridis has been identied and aer heterologous expression in S. lividans and S. coelicolor the desotamide congener G 49 was characterized. 52 A further depsipeptide in the salinamide series, F 50, was isolated from re-cultivation of Streptomyces sp.…”

Marine Spirotetronates: Biosynthetic Edifices That Inspire Drug Discovery

“…Three new members of the lobophorin family have recently been used to trigger cell death in murine tumor fibroblasts through the apoptotic arm of unfolded protein response [96]. Lobophorins CR1 ( 55 ), CR2 ( 60 ), and CR3 ( 61 ) were isolated from Streptomyces sp.…”

“…Lobophorins CR1 ( 55 ) along with known lobophorins A ( 57 ), B ( 58 ), E and F [97] (not pictured) were found to induce endoplasmic reticulum (ER) stress leading to PERK-mediated phosphorylation of eukaryotic initiation factor 2 alpha (elF2α) in oral squamous cell carcinoma. In turn, this leads to activation of the proapoptotic transcription factors, ATF4 and CHOP, ultimately inducing CHOP-dependent apoptosis (Figure 9) [96]. These new members of the lobophorin family were identified using a screen targeting natural products that induce apoptosis through unfolded protein-response.…”

Targeting the unfolded protein response in head and neck and oral cavity cancers

“…Marine environments are teaming with biodiverse microbes that can be harvested for unique renewable enzymes and metabolites. The lobophorins are a great example of such NP's that have been isolated from the Caribbean, the South China Sea, the Costa Rican biota, and the Aviles Canyon off the Asturian coast [95][96][97][98]. Lobophorins are distant relatives of kijanimycin which is also known to have anti-inflammatory and anti-cancer activity.…”

“…Lobophorins are distant relatives of kijanimycin which is also known to have anti-inflammatory and anti-cancer activity. Although few mechanistic studies have been performed to identify potential cellular targets of this class of macrolides, an HTS campaign to identify natural products that activate the UPR at the University of Michigan Center for Chemical Genomics identified three novel lobophorins (CR 1-3) that could activate UPR and cell death in OCSCC cell lines [97]. These lobophorins selectively induced a CHOP-luciferase reporter but not an XBP-1 luciferase reporter, suggesting a bias toward apoptotic UPR signaling.…”