title: Withaferin A modulates the Spindle assembly checkpoint by degradation of Mad2-Cdc20 complex in colorectal cancer cell lines.
abstract: Withania somnifera L. Dunal (Ashwagandha) is used over centuries in the ayurvedic medicines in India. Withaferin A, a withanolide, is the major compound present in leaf extract of the plant which shows anticancer activity against leukemia, breast cancer and colorectal cancer. It arrests the ovarian cancer cells in the G2/M phase in dose dependent manner. In the current study we show the effect of Withaferin A on cell cycle regulation of colorectal cancer cell lines HCT116 and SW480 and its effect on cell fate. Treatment of these cells with this compound leads to apoptosis in a dose dependent manner. It causes the G2/M arrest in both the cell lines. We show that Withaferin A (WA) causes mitotic delay by blocking Spindle assembly checkpoint (SAC) function. Apoptosis induced by Withaferin A is associated with proteasomal degradation of Mad2 and Cdc20, an important constituent of the Spindle Checkpoint Complex. Further overexpression of Mad2 partially rescues the deleterious effect of WA by restoring proper anaphase initiation and keeping more number of cells viable. We hypothesize that Withaferin A kills cancer cells by delaying the mitotic exit followed by inducing chromosome instability.
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India. Electronic address: taniadas.26@gmail.com.
authors.forename: Tania
authors.initials: T
authors.lastname: Das
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India.
authors.forename: Kumar Singha
authors.initials: KS
authors.lastname: Roy
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India.
authors.forename: Tulika
authors.initials: T
authors.lastname: Chakrabarti
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India.
authors.forename: Sibabrata
authors.initials: S
authors.lastname: Mukhopadhyay
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India. Electronic address: susanta@iicb.res.in.
authors.forename: Susanta
authors.initials: S
authors.lastname: Roychoudhury
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D064199:Cdc20 Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000187:drug effects; D002869:Chromosome Aberrations; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D045325:HCT116 Cells / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D064246:Mad2 Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D008941:Spindle Apparatus / Q000187:drug effects*; D054358:Withanolides / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D064199:Cdc20 Proteins; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D054358:Withanolides; C577488:CDC20 protein, human; D046988:Proteasome Endopeptidase Complex; C009684:withaferin A
keywords: Cdc20; Chromosome instability; Mad2; Spindle assembly checkpoint; Withaferin A