Cell death caused by quinazolinone HMJ-38 challenge in oral carcinoma CAL 27 cells: dissections of endoplasmic reticulum stress, mitochondrial dysfunction and tumor xenografts

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Title:	Cell death caused by quinazolinone HMJ-38 challenge in oral carcinoma CAL 27 cells: dissections of endoplasmic reticulum stress, mitochondrial dysfunction and tumor xenografts
Authors:	Lu, Chi-Cheng;Lu, Chi-Cheng;Yan, Jai-Sing;Yang, Jai-Sing;Chian, Jo-Hua;Chiang, Jo-Hua;Hou, Mann-Jen;Hour, Mann-Jen;Lin, Kuei-Li;Lin, Kuei-Li;Lin, Kuei-Li;Lin, Kuei-Li;鍾景光*
Contributors:	生物科技學系
Keywords:	Endoplasmic reticulum stress;HMJ-38;Human oral carcinoma cells;Mitochondrial dysfunction;Tumor xenografts
Date:	2014-07
Issue Date:	2014-11-07 06:45:51 (UTC+0)
Abstract:	BACKGROUND: This investigation clearly clarified the synthesized and antimitotic compound, 2-(3'-methoxyphenyl)-6-pyrrolidinyl-4-quinazolinone (HMJ-38), addressing its target and precise mechanism of action. We hypothesized that HMJ-38 might sensitize apoptotic death of human oral carcinoma CAL 27 cells in vitro and inhibit xenograft tumor growth in vivo. METHODS: Cell viability was assessed utilizing MTT assay. HMJ-38-treated cells represented DNA fragmentation using agarose gel electrophoresis as further evidenced using TUNEL staining. Flow cytometric analyses, immunoblotting and quantitative RT-PCR were applied for protein and gene expression. Antitumor xenograft study was employed. RESULTS: HMJ-38 concentration- and time-dependently reduced viability of CAL 27 cells. The effect of intrinsic molecules was signalized during HMJ-38 exposure with disruption of ΔΨm, MPT pore opening and the release of various events from mitochondria undergoing cell apoptosis. HMJ-38 also markedly facilitated G2/M phase arrest. HMJ-38 stimulated the activation of CDK1 activity that modulated phosphorylation on Ser70 of Bcl-2-mediated mitotic arrest and apoptosis. HMJ-38 triggered intracellular Ca(2+) release and activated related pivotal hallmarks of ER stress. HMJ-38 in nude mice bearing CAL 27 tumor xenografts decreased tumor growth. Furthermore, HMJ-38 enhanced caspase-3 gene expression and protein level in xenotransplanted tumors. CONCLUSIONS: Early roles of mitotic arrest, unfolded protein response and mitochondria-dependent signaling contributed to apoptotic CAL 27 cell demise induced by HMJ-38. In in vivo experiments, HMJ-38 also efficaciously suppressed tumor volume in a xenotransplantation model. GENERAL SIGNIFICANCE: This finding might fully support a critical event for HMJ-38 via induction of apoptotic machinery and ER stress against human oral cancer cells.
Relation:	BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS;1840(7):2310-20.
Appears in Collections:	[生物科技學系] 期刊論文

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