Proteomics

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Spirocyclic dimer (SpiD7) activates unfolded protein response (UPR) to selectively inhibit growth and induce apoptosis of cancer cells


ABSTRACT: 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Pancreatic Cancer

SUBMITTER: Nicholas Woods  

LAB HEAD: Amar Natarajan

PROVIDER: PXD029783 | Pride | 2022-05-20

REPOSITORIES: Pride

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20161114_AN_WT.raw Raw
20161114_AN_WT__F004355_.mzid.gz Mzid
20161114_AN_WT__F004355_.mzid_20161114_AN_WT__F004355_.MGF Mzid
20170202_NW_AN_CloneA.raw Raw
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Spirocyclic dimer SpiD7 activates the unfolded protein response to selectively inhibit growth and induce apoptosis of cancer cells.

Kour Smit S   Rana Sandeep S   Kubica Sydney P SP   Kizhake Smitha S   Ahmad Mudassier M   Muñoz-Trujillo Catalina C   Klinkebiel David D   Singh Sarbjit S   Mallareddy Jayapal Reddy JR   Chandra Surabhi S   Woods Nicholas T NT   Karpf Adam R AR   Natarajan Amarnath A  

The Journal of biological chemistry 20220401 5


The unfolded protein response (UPR) is an adaptation mechanism activated to resolve transient accumulation of unfolded/misfolded proteins in the endoplasmic reticulum. Failure to resolve the transient accumulation of such proteins results in UPR-mediated programmed cell death. Loss of tumor suppressor gene or oncogene addiction in cancer cells can result in sustained higher basal UPR levels; however, it is not clear if these higher basal UPR levels in cancer cells can be exploited as a therapeut  ...[more]

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