Dataset Information

VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis

ABSTRACT: Mitochondria play a critical role in initiating and amplifying ferroptosis. VDAC1 embedded in the mitochondrial outer membrane, exerts a crucial role in regulation of ferroptosis. However, the mechanisms of VDAC1 oligomerization in regulating ferroptosis are not well elucidated. Here, we identified that VSTM2L, a novel VDAC1 binding protein, is positively associated with prostate cancer (PCa) progression, and a key regulator of ferroptosis. Moreover, VSTM2L knockdown in PCa cells enhanced the sensibility of RSL3-induced ferroptosis. Mechanistically, VSTM2L forms complex with VDAC1 and HK2, enhancing their binding affinity and preventing VDAC1 oligomerization, thereby inhibiting ferroptosis and maintaining mitochondria homeostasis in vitro and in vivo. Collectively, our findings reveal a pivotal role for VSTM2L in driving ferroptosis resistance and highlight its potential as a ferroptosis-inducing therapeutic target for the treatment of PCa.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: ping gao

LAB HEAD: Ping Gao

PROVIDER: PXD052173 | Pride | 2025-05-07

REPOSITORIES: Pride

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VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis.

Yang Juan J Lu Xiao X Hao Jing-Lan JL Li Lan L Ruan Yong-Tong YT An Xue-Ni XN Huang Qi-Lai QL Dong Xiao-Ming XM Gao Ping P

Nature communications 20250129 1

Ferroptosis is a form of iron-dependent programmed cell death, which is distinct from apoptosis, necrosis, and autophagy. Mitochondria play a critical role in initiating and amplifying ferroptosis in cancer cells. Voltage-Dependent Anion Channel 1 (VDAC1) embedded in the mitochondrial outer membrane, exerts roles in regulation of ferroptosis. However, the mechanisms of VDAC1 oligomerization in regulating ferroptosis are not well elucidated. Here, we identify that a VDAC1 binding protein V-Set an ...[more]

PMID: 39880844

Similar Datasets

Project description:Mitochondria are subcellular organelles that are more than just the powerhouse of cells, they also dictate if a cell dies or survives. The mitochondrial outer-membrane voltage-dependent anion channel 1 (VDAC1) has been shown to play a crucial role in metabolism and apoptosis, however its involvement in ischemic pathologies and cancer is not clear. Transcriptome analysis of Vdac1-/- mouse embryonic fibroblasts (MEF) highlighted cancer and inflammation as top diesases but also activation of the HIF-1 signaling pathway in normoxia. HIF-1α protein was stable due to ROS accumulation that decreased respiration and glycolysis and maintained basal apoptosis. However, in hypoxia increased activation of ERK in combination with maintenance of respiration and increased glycolysis counterbalanced the deleterious effects of ROS, thereby allowing Vdac1-/- MEF to proliferate better than wild-type MEF. Xenografts of RAS-transformed Vdac1-/- MEF in mice showed stabilization of both HIF-1α and HIF-2α which led to blood vessel destabilization and a strong inflammatory response. Moreover, expression of Cdkn2a, a HIF-1-target and tumor suppressor gene, was strongly decreased. Consequently RAS-transformed Vdac1-/- MEF tumors grew faster than wild-type MEF tumors. These findings provide new perspectives into the understanding of VDAC1 in the function of mitochondria not only in cancer but also in inflammatory diseases. Profiling of VDAC1-/- and wild-type (Wt) Mouse Embryonic Fibroblasts (MEFs) was performed using whole genome mouse microarrays. in normoxic or hypoxic conditions. MEF (Wt and Vdac1-/-) were incubated in normoxia (Nx, ie: 20% O2) or hypoxia (Hx, ie: 1% O2) for 72h and then lysed prior to RNA isolation, labelling and hybridization on microarrays. One color experiment with 2 biological replicates (marked 1 or 2) of the 4 experimental conditions. One condition (MEF WT Nx2) has been removed from the statistical analysis after microarray quality check due to high background. Total of 7 samples.

			Action	DRS
	VDAC1-IPMS.raw	Raw
	VDAC1.msf	Msf
	VSTM2L-IP-MS.raw	Raw
	VSTM2L.msf	Msf