Novel Lobophorins Inhibit Oral Cancer Cell Growth and Induce Atf4- and Chop-Dependent Cell Death in Murine Fibroblasts.
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 UPR-dependent cell death in murine embryonic fibroblast (MEF) cells.
Center for Chemical Genomics, Life Sciences Institute and Departments of Medicinal Chemistry, Chemistry, Microbiology & Immunology, University of Michigan , Ann Arbor, Michigan 48109-2216, United States.
Patricia G
PG
Cruz
Carmen and Ann Adams Department of Pediatrics, Division of Hematology and Oncology, and the Karmanos Cancer Institute Molecular Therapeutics Program, Wayne State University , 2228 Elliman Building, 421 East Canfield, Detroit, Michigan 48201, United States.
Andrew M
AM
Fribley
Carmen and Ann Adams Department of Pediatrics, Division of Hematology and Oncology, and the Karmanos Cancer Institute Molecular Therapeutics Program, Wayne State University , 2228 Elliman Building, 421 East Canfield, Detroit, Michigan 48201, United States.
Justin R
JR
Miller
Center for Chemical Genomics, Life Sciences Institute and Departments of Medicinal Chemistry, Chemistry, Microbiology & Immunology, University of Michigan , Ann Arbor, Michigan 48109-2216, United States.
Martha J
MJ
Larsen
Center for Chemical Genomics, Life Sciences Institute and Departments of Medicinal Chemistry, Chemistry, Microbiology & Immunology, University of Michigan , Ann Arbor, Michigan 48109-2216, United States.
Pamela J
PJ
Schultz
Center for Chemical Genomics, Life Sciences Institute and Departments of Medicinal Chemistry, Chemistry, Microbiology & Immunology, University of Michigan , Ann Arbor, Michigan 48109-2216, United States.
Renju T
RT
Jacob
Instituto Nacional de Biodiversidad (INBio), Heredia, Costa Rica & CIPRONA-Escuela de Química, Universidad de Costa Rica (UCR) , 2061-San José, Costa Rica.
Giselle
G
Tamayo-Castillo
Degenerative Disease Research Program, Center for Cancer Research, Sanford Burnham Prebys Medical Discovery Institute , La Jolla, California 92037, United States.
Randal J
RJ
Kaufman
Center for Chemical Genomics, Life Sciences Institute and Departments of Medicinal Chemistry, Chemistry, Microbiology & Immunology, University of Michigan , Ann Arbor, Michigan 48109-2216, United States.
David H
DH
Sherman
ATF4; CHOP; ER stress; UPR; anticancer; lobophorin; natural products; oral cancer; oral squamous cell carcinoma