PXD029783-1

PXD029783 is an original dataset announced via ProteomeXchange.

Title	Spirocyclic dimer (SpiD7) activates unfolded protein response (UPR) to selectively inhibit growth and induce apoptosis of cancer cells
Description	Protein homeostasis is maintained by a combination of tightly controlled processes which include synthesis, folding, trafficking and degradation. Transient accumulation of unfolded / misfolded proteins in the endoplasmic reticulum (ER) due to cell intrinsic and / or extrinsic signals results in the activation of unfolded protein response (UPR), an adaptation mechanism. Failure to resolve the transient accumulation results in UPR mediated programmed cell death. Loss of tumor suppressor gene or oncogene addiction in cancer cells result in a sustained higher basal UPR levels. This higher basal UPR levels in cancer cells when compared to normal cells provides a therapeutic window that can be exploited by UPR activators. Here we explored covalent modification of surface exposed cysteine (SEC) residues to simulate unfolded / misfolded proteins and induce UPR activation. A proteome-wide click-pulldown-MS study using an alkyne tagged isatin-derived spirocyclic -methylene--butyrolactone analog identified > 330 protein targets that were covalently modified. Evaluation for UPR activation with a set of analogs that can covalently modify SECs identified a spirocyclic -methylene--butyrolactone dimer (SpiD7) as a UPR activator. SpiD7 induced XBP1 splicing protected normal cells from caspase-mediated apoptosis, no such induction was observed in cancer cells, which resulted in caspase-mediated apoptosis in cancer cells. SpiD7 inhibits growth of high-grade serous carcinoma (HGSC) cell lines ~3-15 fold more potently than immortalized fallopian tube epithelial (normal) cells and reduced clonogenic growth of HGSC cell lines. Our results suggest that induction of UPR by covalent modification of SEC residues is a cancer cell vulnerability and can be exploited to discover novel therapeutics.
HostingRepository	PRIDE
AnnounceDate	2022-05-20
AnnouncementXML	Submission_2022-05-20_02:09:16.742.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD029783
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Nicholas Woods
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-11-17 01:21:48	ID requested
⏵ 1	2022-05-20 02:09:17	announced

Kour S, Rana S, Kubica SP, Kizhake S, Ahmad M, Mu, ñ, oz-Trujillo C, Klinkebiel D, Singh S, Mallareddy JR, Chandra S, Woods NT, Karpf AR, Natarajan A, Spirocyclic dimer SpiD7 activates the unfolded protein response to selectively inhibit growth and induce apoptosis of cancer cells. J Biol Chem, 298(5):101890(2022) [pubmed]

submitter keyword: Unfolded Protein Response (UPR)

Amar Natarajan
contact affiliation	Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center
contact email	anatarajan@unmc.edu
lab head
Nicholas Woods
contact affiliation	University of Nebraska Medical Center
contact email	nicholas.woods@unmc.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD029783
     1. Label: PRIDE project
     2. Name: Spirocyclic dimer (SpiD7) activates unfolded protein response (UPR) to selectively inhibit growth and induce apoptosis of cancer cells