Coupling endoplasmic reticulum stress to the cell death program in mouse melanoma cells: effect of curcumin.
The microenvironment of cancerous cells includes endoplasmic reticulum (ER) stress the resistance to which is required for the survival and growth of tumors. Acute ER stress triggers the induction of a family of ER stress proteins that promotes survival and/or growth of the cancer cells, and also confers resistance to radiation and chemotherapy. Prolonged or severe ER stress, however, may ultimately overwhelm the cellular protective mechanisms, triggering cell death through specific programmed cell death (pcd) pathways. Thus, downregulation of the protective stress proteins may offer a new therapeutic approach to cancer treatment. In this regard, recent reports have demonstrated the roles of the phytochemical curcumin in the inhibition of proteasomal activity and triggering the accumulation of cytosolic Ca(2+) by inhibiting the Ca(2+)-ATPase pump, both of which enhance ER stress. Using a mouse melanoma cell line, we investigated the possibility that curcumin may trigger ER stress leading to programmed cell death. Our studies demonstrate that curcumin triggers ER stress and the activation of specific cell death pathways that feature caspase cleavage and activation, p23 cleavage, and downregulation of the anti-apoptotic Mcl-1 protein.
Bakhshi
Jason
J
Terra Linda High School, 320 Nova Albion Way, San Rafael, CA 94903, USA.
Weinstein
Lee
L
Poksay
Karen S
KS
Nishinaga
Brian
B
Bredesen
Dale E
DE
Rao
Rammohan V
RV
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D003474:Curcumin / Q000494:pharmacology*; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism
D000970:Antineoplastic Agents; D002614:Chelating Agents; C497250:Ddit3 protein, mouse; D015852:Eukaryotic Initiation Factor-2; D019253:Proto-Oncogene Proteins c-bcl-2; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D051742:Transcription Factor CHOP; D004533:Egtazic Acid; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D003474:Curcumin