Glutaminase inhibitor compound 968 inhibits cell proliferation and sensitizes paclitaxel in ovarian cancer.
Our overall goal was to investigate the anti-tumor activity of the glutaminase 1 (GLS1) Inhibitor compound 968 in ovarian cancer cells. The human ovarian cancer cell lines, HEY, SKOV3 and IGROV-1 were used. Cell proliferation was assessed by MTT assay after treatment with compound 968. Cell cycle progression and Annexin V expression were evaluated using Cellometer. Western blotting was performed to determine changes in GLS1, cellular stress and cell cycle checkpoints. Reactive oxygen species (ROS) and glutamate dehydrogenase (GDH) activity were assessed by ELISA assay. Compound 968 significantly inhibited cell proliferation and the expression of GLS1 in a dose-dependent manner in all three ovarian cancer cell lines. Compound 968 induced G1 phase cell cycle arrest and apoptosis. Treatment with compound 968 increased ROS levels and induced the protein expression of calnexin, binding immunoglobulin protein (BiP) and protein kinase RNA-like endoplasmic reticulum kinase (PERK). Deprivation of glutamine increased the sensitivity of cells to paclitaxel, and compound 968 sensitized cells to the anti-proliferative effects of paclitaxel. Compound 968 inhibited cell growth in ovarian cancer cells through induction of G1 phase cell cycle arrest, apoptosis and cellular stress, suggesting that targeting GLS1 provide a novel therapeutic strategy for ovarian cancer.
Department of Gynecologic Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical SciencesJinan, Shandong, China; Division of Gynecological Oncology, University of North CarolinaChapel Hill, NC, USA.
Lingqin
L
Yuan
Department of Gynecologic Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences Jinan, Shandong, China.
Xiugui
X
Sheng
Division of Gynecological Oncology, University of North Carolina Chapel Hill, NC, USA.
Leslie H
LH
Clark
Department of Gynecologic Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical SciencesJinan, Shandong, China; Division of Gynecological Oncology, University of North CarolinaChapel Hill, NC, USA.
Lu
L
Zhang
Department of Gynecologic Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical SciencesJinan, Shandong, China; Division of Gynecological Oncology, University of North CarolinaChapel Hill, NC, USA.
Hui
H
Guo
Division of Gynecological Oncology, University of North Carolina Chapel Hill, NC, USA.
Hannah M
HM
Jones
Division of Gynecological Oncology, University of North Carolina Chapel Hill, NC, USA.
Adam K
AK
Willson
Division of Gynecological Oncology, University of North CarolinaChapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North CarolinaChapel Hill, NC, USA.
Paola A
PA
Gehrig
Division of Gynecological Oncology, University of North CarolinaChapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North CarolinaChapel Hill, NC, USA.
Chunxiao
C
Zhou
Division of Gynecological Oncology, University of North CarolinaChapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North CarolinaChapel Hill, NC, USA.
Victoria L
VL
Bae-Jump
Glutaminase; apoptosis; cellular stress; compound 968; ovarian cancer