title: 7, 8-diacetoxy-4-methylcoumarin induced cell death in human tumor cells is influenced by calreticulin.
abstract: Calreticulin (CRT), an endoplasmic reticulum resident protein demonstrates transacetylase activity in presence of 7, 8 diacetoxy-4-methyl coumarin (DAMC) in vitro. To investigate the possible role of CRT and DAMC mediated protein acetylation in cells, we investigated the effects of DAMC in tumor cells with different levels of CRT. DAMC was more toxic (clonogenicity, metabolic viability and proliferation) to human glioma cells (BMG-1) expressing low endogenous CRT level as compared to head and neck carcinoma cells (KB) with a high CRT level. The cytotoxicity was accompanied by loss of mitochondrial membrane potential in both the cells, which correlated with corresponding changes in the levels of pro-apoptotic (Bax) and anti-apoptotic (NFkB) regulators. Manipulation of CRT protein level in KB cells by application of small RNA interference enhanced the sensitivity by four folds while over expression of CRT in BMG-1 cells reduced their sensitivity to DAMC by ~20% strongly suggesting the influence of CRT on DAMC induced cytotoxicity. The partial rescue of CROE cells from DAMC induced toxicity was accompanied by changes in NFkB levels and over all protein acetylation status, besides increase in the NADPH-cytochrome c reductase activity related to its well known antioxidant property. Since CRT is over-expressed in cancer cells, which are generally resistant to radio- and chemotherapy; targeting CRT transacetylase system, may be an attractive approach for increasing the efficacy of anticancer therapies.
authors.affiliation: Institute of Nuclear Medicine and Allied Sciences, Brig. S. K. Majumdar Marg, Timarpur, Delhi, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
authors.forename: Anant Narayan
authors.initials: AN
authors.lastname: Bhatt
authors.forename: Abdullah
authors.initials: A
authors.lastname: Farooque
authors.forename: Suchit
authors.initials: S
authors.lastname: Khanna
authors.forename: Divya
authors.initials: D
authors.lastname: Khaitan
authors.forename: Mohan B
authors.initials: MB
authors.lastname: Arya
authors.forename: Anu
authors.initials: A
authors.lastname: Arya
authors.forename: Ashish
authors.initials: A
authors.lastname: Dhawan
authors.forename: Hanumantharao G
authors.initials: HG
authors.lastname: Raj
authors.forename: Daman
authors.initials: D
authors.lastname: Saluja
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Prasad
authors.forename: Virinder S
authors.initials: VS
authors.lastname: Parmar
authors.forename: Bilikere S
authors.initials: BS
authors.lastname: Dwarakanath
mesh_terms: D000107:Acetylation / Q000187:drug effects; D037282:Calreticulin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C114369:7,8-diacetoxy-4-methylcoumarin; D037282:Calreticulin; D003374:Coumarins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species