LKB1 is commonly thought of as a tumor suppressor gene because its hereditary mutation is responsible for a cancer syndrome,and somatic inactivation of LKB1 is found in nonsmall cell lung cancer,melanoma,and cervical ...LKB1 is commonly thought of as a tumor suppressor gene because its hereditary mutation is responsible for a cancer syndrome,and somatic inactivation of LKB1 is found in nonsmall cell lung cancer,melanoma,and cervical cancers.However,unlike other tumor suppressors whose main function is to either suppress cell proliferation or promote cell death,one of the functions of LKB1-regulated AMPK signaling is to suppress cell proliferation in order to promote cell survival under energetic stress conditions.This unique,pro-survival function of LKB1 has led to the discovery of reagents,such as phenformin,that specifically exploit the vulnerability of LKB1-null cells in their defect in sensing energetic stress.Such targeted agents represent a novel treatment strategy because they induce cell killing when LKB1 is absent.This review article summarizes various vulnerabilities of LKB1-mutant cells that have been reported in the literature and discusses the potential of using existing or developing novel reagents to target cancer cells with defective LKB1.展开更多
Ras homolog gene family,member A(RhoA)is a small GTPase that plays critical roles in several essential cell functions,such as migration,adhesion,proliferation,and gene expression.1 RhoA switches between a GTP-bound ac...Ras homolog gene family,member A(RhoA)is a small GTPase that plays critical roles in several essential cell functions,such as migration,adhesion,proliferation,and gene expression.1 RhoA switches between a GTP-bound active form and a GDP-bound inactive form.The activated RhoA directly interacts with its downstream effectors,such as Rho kinase(ROCK)to regulate actomyosin dynamics,or mDia1 to control stress fiber and filopodia formation.The activity of RhoA is primarily regulated by guanine nucleotide exchange factors(GEFs),GTPaseactivating protein(GAP),and guanine nucleotidedissociation inhibitors(GDIs).展开更多
基金This work was supported in part by R01-CA140571,P01 CA116676Anise McDaniel Brock Scholar fund to WZ,1RO1CA142858 to A.M.,and P30CA138292 to Winship Cancer Institute.
文摘LKB1 is commonly thought of as a tumor suppressor gene because its hereditary mutation is responsible for a cancer syndrome,and somatic inactivation of LKB1 is found in nonsmall cell lung cancer,melanoma,and cervical cancers.However,unlike other tumor suppressors whose main function is to either suppress cell proliferation or promote cell death,one of the functions of LKB1-regulated AMPK signaling is to suppress cell proliferation in order to promote cell survival under energetic stress conditions.This unique,pro-survival function of LKB1 has led to the discovery of reagents,such as phenformin,that specifically exploit the vulnerability of LKB1-null cells in their defect in sensing energetic stress.Such targeted agents represent a novel treatment strategy because they induce cell killing when LKB1 is absent.This review article summarizes various vulnerabilities of LKB1-mutant cells that have been reported in the literature and discusses the potential of using existing or developing novel reagents to target cancer cells with defective LKB1.
基金supported in part by R01-CA140571,P01 CA116676,Anise McDaniel Brock Scholar fund to WZ,1R01CA142858 to AM,and P30CA138292 to Winship Cancer Institute。
文摘Ras homolog gene family,member A(RhoA)is a small GTPase that plays critical roles in several essential cell functions,such as migration,adhesion,proliferation,and gene expression.1 RhoA switches between a GTP-bound active form and a GDP-bound inactive form.The activated RhoA directly interacts with its downstream effectors,such as Rho kinase(ROCK)to regulate actomyosin dynamics,or mDia1 to control stress fiber and filopodia formation.The activity of RhoA is primarily regulated by guanine nucleotide exchange factors(GEFs),GTPaseactivating protein(GAP),and guanine nucleotidedissociation inhibitors(GDIs).
