title: CSTMP induces apoptosis and mitochondrial dysfunction in human myeloma RPMI8226 cells via CHOP-dependent endoplasmic reticulum stress.
abstract: BACKGROUND
  The natural product tetramethylpyrazine (TMP) and resveratrol have a variety of biologic activities, including anti-cancer effects. However the pharmacological function of CSTMP (a newly designed and synthesized TMP and resveratrol derivative) in cancer have not been elucidated.
  
  
  METHODS
  In RPMI8226 cells, the cytotoxic effects and apoptosis were detected by MTT and Double staining for Annexin V-FITC and propidium iodide (PI). The protein and mRNA expression levels were detected by Real Time PCR and Western blot, respectively. The localization of cleaved caspase-12 was evaluated by immunofluorescent staining. The activation of caspase were measured by colorimetric assays and Western blot.
  
  
  RESULTS
  CSTMP showed significantly cytotoxic effects and induced apoptosis in RPMI8226 cells. Caspase activation, Cytochrome c release and Bax, Bcl-2 and Bcl-XL levels analyses demonstrated that the anti-cancer effect of CSTMP in RPMI8226 cells was mediated by promoting caspase- and mitochondria-dependent apoptosis. In addition, CSTMP induced the increased expression of endoplasmic reticulum (ER) stress related proteins (CHOP, GRP78, GRP94 and cleaved caspase-12) and the activation of multiple branches of ER stress transducers (PERK-eIF2α, IRE1α and ATF6). Moreover, knockdown of CHOP by siRNA markedly inhibited CSTMP-induced cytotoxic effects, caspases activity and mitochondrial dysfunction in RPMI8226 cells.
  
  
  CONCLUSIONS
  Our results indicated that CSTMP could induce apoptosis and mitochondrial dysfunction in RPMI8226 cells via CHOP-dependent ER stress.
authors.affiliation: College of Life Sciences, Sichuan University, Chengdu, Sichuan, 610064, PR China.
authors.forename: Xing
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Cardiology, Hainan General Hospital, Haikou, Hainan, 570102, PR China.
authors.forename: Wang
authors.initials: W
authors.lastname: Liao
authors.affiliation: School of Foreign Languages and Literature, Wuhan University, Wuhan, Hubei, 430072, PR China.
authors.forename: Jialing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Hematology, Zhumadian Central Hospital, Zhumadian, Henan 463000, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Hematology, Zhumadian Central Hospital, Zhumadian, Henan 463000, PR China.
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Hematology, Zhumadian Central Hospital, Zhumadian, Henan 463000, PR China.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Hematology, Zhumadian Central Hospital, Zhumadian, Henan 463000, PR China.
authors.forename: Chunling
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Hematology, Zhumadian Central Hospital, Zhumadian, Henan 463000, PR China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Department of Dermatology, Maternal and Child Health Care Hospital of Hainan Province, Haikou, Hainan, 570206, PR China. Electronic address: dingyanhn@163.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D011719:Pyrazines / Q000494:pharmacology*; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: C000613321:2-(2-chlorostyryl)-3,5,6-trimethylpyrazine; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D011719:Pyrazines; D013267:Stilbenes; D051742:Transcription Factor CHOP; D045304:Cytochromes c; D020169:Caspases; D000077185:Resveratrol
keywords: Apoptosis; CHOP; CSTMP; ER stress; Mitochondrial dysfunction; Multiple myeloma