ArticleResearch square2026
Inhibition of SIK2 and SIK3 induces adaptive ER-phagy and creates a therapeutic vulnerability in ovarian cancer.
Article in Research square, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
0 citing papers in PubMed.
No citing paper in PubMed yet.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors.
Funding
Abstract
Cancer cells depend on protein quality control pathways to survive intrinsic and microenvironmental stress. Endoplasmic reticulum (ER)-selective autophagy (ER-phagy) maintains ER homeostasis by eliminating damaged ER and misfolded protein aggregates during ER stress. How ER stress-induced ER-phagy is regulated in cancer remains poorly understood. Salt-inducible kinases SIK2 and SIK3 (SIK2/3) are serine/threonine kinases implicated in metabolic regulation and cancer cell survival, but their roles in ER stress signaling and ER-phagy have not previously been studied. Here, we show that genetic or pharmacologic inhibition of SIK2/3 induces proteotoxic stress and activates the unfolded protein response through the PERK and IRE1 pathways, with predominant engagement of PERK and its downstream effector ATF4. SIK2/3 inhibition promotes ER-phagy by upregulating the ER-phagy receptor CCPG1 in an ATF4-dependent manner and increasing autophagic flux, thereby enabling cancer cell survival under stress. Disruption of this adaptive response results in the accumulation of polyubiquitinated protein aggregates, induction of CHOP, and apoptotic cell death in ovarian cancer cells. Importantly, combined treatment with the dual SIK2/3 inhibitor GRN-300 and the autophagy inhibitor chloroquine synergistically enhanced proteotoxic stress, reduced cell viability (combination index < 0.9), and triggered CHOP-dependent apoptosis. In ovarian cancer xenograft models, GRN-300 plus chloroquine markedly suppressed tumor growth and significantly prolonged survival compared with either monotherapy. Together, these findings identify SIK2/3 as key regulators of ER stress-induced ER-phagy and reveal a targetable stress-adaptation pathway that can be exploited therapeutically in ovarian cancer.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.