title: Tumor necrosis factor-α sensitizes breast cancer cells to natural products with proteasome-inhibitory activity leading to apoptosis.
abstract: The inflammatory microenvironment plays an important role in the process of tumor development. Tumor necrosis factor-α (TNF-α), a key pro-inflammatory cytokine, has a significant role in this process. Natural medicinal products such as Withaferin A (WA) and Celastrol (Cel) have shown anti-cancer and anti-inflammatory properties that can be attributed to multiple mechanisms including, but not limited to, apoptosis induction due to the inhibition of proteasomal activities. This study aimed to investigate the effects of TNF-α in combination with WA or Cel in vitro in MDA-MB-231 breast cancer cells. TNF-α, when combined with WA or Cel, activated caspase-3 and -9 and downregulated XIAP in a dose-dependent manner, leading to induction of apoptosis in MDA-MB-231 breast cancer cells. The combination also caused accumulation of the proteasomal target protein IκBα, resulting in inhibition of the nuclear translocation of nuclear factor-κB (NF-κB). Taken together, these results suggest that TNF-α could sensitize breast cancer cells MDA-MB-231 to WA and Cel, at least in part, through inhibiting the activation of NF-κB signaling, leading to XIAP inhibition with subsequent upregulation of caspase-3 and -9 activities. Thus, the anti-cancer activities of TNF-α are enhanced when combined with the natural proteasome inhibitors, WA or Cel.
authors.affiliation: Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong Province, China; Department of Pathology and Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong Province, China.
authors.forename: Wenli
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Pathology and Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Rahul R
authors.initials: RR
authors.lastname: Deshmukh
authors.affiliation: Department of Pathology, Guangzhou Medical University, Guangzhou, Guangdong Province, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Long
authors.affiliation: Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong Province, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangdong Provincial Key Laboratory of Urology, Guangzhou, Guangdong Province, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Ji
authors.affiliation: Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangdong Provincial Key Laboratory of Urology, Guangzhou, Guangdong Province, China.
authors.forename: Guohua
authors.initials: G
authors.lastname: Zeng
authors.affiliation: Department of Pathology, Guangzhou Medical University, Guangzhou, Guangdong Province, China.
authors.forename: Xianliang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pathology, Guangzhou Medical University, Guangzhou, Guangdong Province, China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan, United States of America; Departments of Oncology and Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001688:Biological Products / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D053978:Pentacyclic Triterpenes; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D054358:Withanolides / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D001688:Biological Products; D051034:Inhibitor of Apoptosis Proteins; D053978:Pentacyclic Triterpenes; D051996:Transcription Factor RelA; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; D054358:Withanolides; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D053148:Caspase 3; D053453:Caspase 9; D046988:Proteasome Endopeptidase Complex; C009684:withaferin A; C050414:celastrol