title: Human cytomegalovirus (HCMV) IE1 plays role in resistance to apoptosis with etoposide in cancer cell line by Cdk2 accumulation.
abstract: Human cytomegalovirus (HCMV) has many strategies to survive the attack of the host. HCMV infection of host cells induces cellular activation and disturbance of the cell cycle. It is possible that HCMV modulates the behavior of certain cancer cells that are susceptible to HCMV infection. This study was performed to identify the possible mechanism of resistance to apoptotic stimuli in some cancer cell lines by HCMV infection. HCMV-infected cancer cells showed resistance to apoptosis induced by the topoisomerase II inhibitor etoposide. UMG1-2, which constitutively expresses HCMV immediate-early protein-1 (IE1), had resistance to apoptosis induced by etoposide as compared with the parental cell line U373MG. Measurement of caspases activity with fluorogenic substrates in etoposide-treated U373MG and UMG1-2 cells and the direct activation of caspase-3 with peptides containing arginine-glycine-aspartate in U373MG and UMG1-2 cells revealed that the inhibition level of apoptosis by HCMV IE1 would be upstream of caspase-3 in the caspase cascade pathway. Cellular expression of Cdk2 was increased in UMG1- 2 after etoposide treatment while the expression of E2F-1 in UMG1-2 was decreased as compared with that in U373MG. The Cdk2 inhibitor, roscovitine, decreased the resistance to apoptosis on etoposide-treated UMG1-2. These results suggest that aberrant HCMV infection confers resistance to anticancer drugs on some cancer cells and protects cells from apoptosis, possibly due to the deregulation of cyclin-dependent kinase by HCMV immediate-early protein.
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine and Institute of Endemic Disease, Seoul National University Medical Research Center, Seoul, Republic of Korea.
authors.forename: Jinhee
authors.initials: J
authors.lastname: Kim
authors.forename: Ye Jin
authors.initials: YJ
authors.lastname: Kwon
authors.forename: Eun-Suk
authors.initials: ES
authors.lastname: Park
authors.forename: Bohyun
authors.initials: B
authors.lastname: Sung
authors.forename: Jung Heon
authors.initials: JH
authors.lastname: Kim
authors.forename: Chung-Gyu
authors.initials: CG
authors.lastname: Park
authors.forename: Eung-Soo
authors.initials: ES
authors.lastname: Hwang
authors.forename: Chang-Yong
authors.initials: CY
authors.lastname: Cha
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2; D003587:Cytomegalovirus / Q000502:physiology*; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000502:physiology*; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D014157:Transcription Factors / Q000096:biosynthesis; D014764:Viral Proteins
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D004791:Enzyme Inhibitors; C088645:IE1 protein, cytomegalovirus; D017874:Immediate-Early Proteins; D011687:Purines; D014157:Transcription Factors; D014764:Viral Proteins; D000077546:Roscovitine; D005047:Etoposide; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases