title: Regulation of topoisomerase II alpha and beta in HIV-1 infected and uninfected neuroblastoma and astrocytoma cells: involvement of distinct nordihydroguaretic acid sensitive inflammatory pathways.
abstract: The activity of Topoisomerase II alpha and beta isoforms is tightly regulated during different phases of cell cycle. In the present study, the action of anti-inflammatory agents, nordihydroguaretic acid (NDGA) is analyzed in HIV-1 infected CXCR4(+), CCR5(+) and CD4(-) SK-N-SH neuroblastoma, CXCR4(+), CCR5(+) and CD4(-) 1321N1 astrocytoma and CXCR4(+), CCR5(+/-) and CD4(-) GO-G-CCM glioblastoma cell lines. In SK-N-SH and 1321N1 the expression of Topoisomerase II alpha is concomitant with that of LOX-5 and is highly sensitive to NDGA, while the Topoisomerase II beta is expressed along with TNFalpha and exhibits low sensitivity to NDGA, suggesting distinct pathways of regulation for the two isoforms. HIV-1 infection in these cells enhanced the expression of Topo II alpha and beta. Further, the regulation of Topo II beta and TNFalpha in infected and uninfected SK cells is distinctly different. HIV-1 gp120 derived peptides could block HIV-1 mediated inflammation and Topoisomerase II alpha and beta expression, suggesting the viral mediated response. A combination of NDGA, gp-120 derived peptides and AZT has completely blocked the viral replication, suggesting the enhancement of potency of AZT under the suppression of inflammatory response. In contrast, the expression of Topo II alpha and beta was stimulated by NDGA in GO-G-CCM cells showing distinct regulatory pathway in these cells that was resistant to HIV-1 infection. This suggests the requirement of inflammatory response for productive viral infection. In summary, an induction of co-receptor mediated inflammatory response can distinctly enhance regulated expression of the cellular Topo II alpha and beta and promote productive infection in neurons and astrocytes.
authors: Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India.
authors: Raj Kumar
authors: RK
authors: Mandraju
authors: Anand K
authors: AK
authors: Kondapi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D001254:Astrocytoma / Q000201:enzymology / Q000473:pathology / Q000821:virology*; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D009637:Masoprocol / Q000494:pharmacology*; D051379:Mice; D009447:Neuroblastoma / Q000201:enzymology / Q000473:pathology / Q000821:virology*; D000075223:Poly-ADP-Ribose Binding Proteins; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D000075223:Poly-ADP-Ribose Binding Proteins; D009637:Masoprocol; D004250:DNA Topoisomerases, Type II; C000618814:TOP2B protein, human