title: BH3 mimetic ABT-737 sensitizes colorectal cancer cells to ixazomib through MCL-1 downregulation and autophagy inhibition.
abstract: The proteasome inhibitor MLN9708 is an orally administered drug that is hydrolyzed into its active form, MLN2238 (ixazomib). Compared with Bortezomib, MLN2238 has a shorter proteasome dissociation half-life and a lower incidence and severity of peripheral neuropathy, which makes it an attractive candidate for colorectal cancer treatment. In the present study, we observed that MLN2238 induced autophagy, as evidenced by conversion of the autophagosomal marker LC3 from LC3I to LC3II, in colorectal cancer cell lines. Mcl-1, an anti-apoptotic Bcl-2 family protein, was markedly elevated after treating a colorectal cancer cell line with MLN2238. We proved that inhibiting Mcl-1 expression enhances MLN2238 induced apoptosis and negatively regulates autophagy. Co-administration of BH3 mimetic ABT-737 with MLN2238 synergistically kills colorectal cancer cells through MCL-1 neutralization and autophagy inhibition. Furthermore, the synergistic killing effect of the combination therapy is correlated with P53 status in colorectal cancer. These data highlight that the combination of ABT-737 with MLN9708 is a promising therapeutic strategy for human colorectal cancer.
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center and Department of Oncology, Shanghai Medical College, Fudan University Shanghai 200032, China.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center and Department of Oncology, Shanghai Medical College, Fudan University Shanghai 200032, China.
authors.forename: Juefeng
authors.initials: J
authors.lastname: Wan
authors.affiliation: Department of Integrative Medicine and Neurobiology, Institute of Acupuncture Research, Institute of Brain Science, Shanghai Medical College, Fudan University Shanghai 200032, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Xiao
authors.affiliation: Department of Radiation Oncology, Kimmel Cancer Center, Thomas Jefferson University Philadelphia, PA, USA.
authors.forename: Darryll
authors.initials: D
authors.lastname: Barkhouse
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center and Department of Oncology, Shanghai Medical College, Fudan University Shanghai 200032, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center and Department of Oncology, Shanghai Medical College, Fudan University Shanghai 200032, China.
authors.forename: Guichao
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, Kimmel Cancer Center, Thomas Jefferson University Philadelphia, PA, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Lu
authors.affiliation: Department of Radiation Oncology, Fudan University Shanghai Cancer Center and Department of Oncology, Shanghai Medical College, Fudan University Shanghai 200032, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
keywords: ABT-737; Colorectal cancer; MCL-1; MLN9708; autophagy