Dataset Information

Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS sensing pathway

ABSTRACT: Multiple anticancer drugs have been proposed to cause cell death, in part, by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs exactly how the resultant ROS function and are sensed is poorly understood. It remains unclear which proteins the ROS modify and their roles in drug sensitivity/resistance. To answer these questions, we examined 11 anticancer drugs with an integrated proteogenomic approach identifying many unique targets but also shared ones–including ribosomal components, suggesting common mechanisms by which drugs regulate translation. We focus on CHK1 which we find is a nuclear H2O2 sensor that launches a cellular program to dampen ROS. CHK1 phosphorylates the mitochondrial-DNA binding protein SSBP1 to prevent its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS sensing pathway–required to resolve nuclear H2O2 accumulation and mediate resistance to platinum-based agents in ovarian cancers.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Leukocyte, Bone Marrow

DISEASE(S): Acute Leukemia

SUBMITTER: JUNBING ZHANG

LAB HEAD: Liron Bar-Peled

PROVIDER: PXD041138 | Pride | 2024-06-16

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	0045_20210919_JunBing_CDM_IA-DTB_SP3_RTS_FAIMS_FF_180min_frac_08.raw	Raw
	0045_20210919_JunBing_CDM_IA-DTB_SP3_RTS_FAIMS_FF_180min_frac_09.raw	Raw
	0045_20210919_JunBing_CDM_IA-DTB_SP3_RTS_FAIMS_FF_180min_frac_10.raw	Raw
	0045_20210919_JunBing_CDM_IA-DTB_SP3_RTS_FAIMS_FF_180min_frac_11.raw	Raw
	0045_20210919_JunBing_CDM_IA-DTB_SP3_RTS_FAIMS_FF_180min_frac_12.raw	Raw

Items per page:

1 - 5 of 74

Publications

Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway.

Zhang Junbing J Simpson Claire M CM Berner Jacqueline J Chong Harrison B HB Fang Jiafeng J Ordulu Zehra Z Weiss-Sadan Tommy T Possemato Anthony P AP Harry Stefan S Takahashi Mariko M Yang Tzu-Yi TY Richter Marianne M Patel Himani H Smith Abby E AE Carlin Alexander D AD Hubertus de Groot Adriaan F AF Wolf Konstantin K Shi Lei L Wei Ting-Yu TY Dürr Benedikt R BR Chen Nicholas J NJ Vornbäumen Tristan T Wichmann Nina O NO Mahamdeh Mohammed S MS Pooladanda Venkatesh V Matoba Yusuke Y Kumar Shaan S Kim Eugene E Bouberhan Sara S Oliva Esther E Rueda Bo R BR Soberman Roy J RJ Bardeesy Nabeel N Liau Brian B BB Lawrence Michael M Stokes Matt P MP Beausoleil Sean A SA Bar-Peled Liron L

Cell 20230515 11

Multiple anticancer drugs have been proposed to cause cell death, in part, by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs, exactly how the resultant ROS function and are sensed is poorly understood. It remains unclear which proteins the ROS modify and their roles in drug sensitivity/resistance. To answer these questions, we examined 11 anticancer drugs with an integrated proteogenomic approach identifying not only many unique tar ...[more]

PMID: 37192619

Similar Datasets

Project description:Aims: We explore the role of elevated O2-:H2O2 ratio as a prosurvival signal in glioma-propagating cells (GPCs). We hypothesize that depleting this ratio sensitizes GPCs to apoptotic triggers. Results: We observed that elevated O2-:H2O2 ratio conferred enhanced resistance in GPCs, and depletion of this ratio by pharmacological and genetic methods sensitized cells to apopotic triggers. We established the ROS Index as a quantitative measure of normalized O2-:H2O2 ratio and determined its utility in predicting chemosensitivity. Importantly, mice implanted with GPCs of reduced ROS Index demonstrated extended survival. Analysis of tumor sections revealed effective targeting of CD133- and nestin-expressing neural precursors. Furthermore, we established the Connectivity Map to interrogate a gene signature derived from varied ROS Index for patterns of association with individual patient gene expression in 2 clinical databases. We showed that patients with reduced ROS Index demonstrate better survival. These data provide clinical evidence for the viability of our O2-:H2O2-mediated chemosensitivity profiles. Innovation and Conclusion: Gliomas are notoriously recurrent and highly infiltrative, and have been shown to arise from stem-like cells. We implicate elevated O2-:H2O2 ratio as a prosurvival signal in GPC self-renewal and proliferation. The ROS Index provides quantification of O2-:H2O2-mediated chemosensitivity, an advancement in a previously qualitative field. Intriguingly, glioma patients with reduced ROS Index correlate with longer survival and the Proneural molecular classification, a feature frequently associated with tumors of better prognosis. These data emphasize the feasibility of manipulating the O2-:H2O2 ratio as a therapeutic strategy. Total RNA from primary neurosphere culture of brain tumor specimens treated with DPI and DDC as well as non-treated CD133+ and CD133- fractions were compared. Specimens were obtained from 3 patients and replicate arrays were performed for all 3 neurosphere cultures.