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Dissociation of MIF-rpS3 complex and sequential NF-κB activation is involved in IR-induced metastatic conversion of
HyeSook Youn1,2, Beomseok Son3, Wanyeon Kim1,2
1Department of Biological Sciences, Pusan National University, Busan, 609-735, Republic of Korea.
Abstract:
Frequent relapse and spreading of tumors during radiotherapy are principal obstacles to treatment of non-small cell lung cancer (NSCLC). In this study, we aimed to investigate how macrophage migration inhibitory factor (MIF) which is expressed at high levels in metastatic and primary lung cancer cells could regulate NSCLC metastasis in response to ionizing radiation (IR). The results indicated that MIF and ribosomal protein S3 (rpS3) were shown to be connected to inflammation, proliferation, and metastasis of NSCLC via IR-induced activation of the NF-κB pathway. Under unirradiated conditions, MIF physically established a complex with rpS3. MIF-rpS3 dissociation induced by IR activated NF-κB and made the expression of target genes of this factor transactivated in two NSCLC cell lines, A549, and NCI-H358. We also found that IR-induced dissociation of this complex led to increased secretion of pro-inflammatory cytokines and modulated the expression of epithelial-mesenchymal transition marker proteins. Finally, the effects of IR-induced dissociation of the MIF-rpS3 complex on tumor metastasis were confirmed by in vivo xenograft studies. Taken together, the present study revealed that dissociation of the MIF-rpS3 complex and subsequent activation of NF-κB is a critical post-IR exposure event that accounts for IR-induced metastatic conversion of NSCLC.
Insights
Ionizing radiation (IR) can trigger non-small cell lung cancer (NSCLC) metastasis by dissociating the MIF-rpS3 complex, activating the NF-κB pathway. This molecular event promotes tumor cell inflammation and spread, hindering radiotherapy effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy Research
Background:
- Non-small cell lung cancer (NSCLC) frequently relapses and metastasizes during radiotherapy, representing a significant clinical challenge.
- Macrophage migration inhibitory factor (MIF) is highly expressed in lung cancer and implicated in metastasis.
Purpose of the Study:
- To investigate the role of MIF in regulating NSCLC metastasis following ionizing radiation (IR).
- To elucidate the molecular mechanisms linking MIF, ribosomal protein S3 (rpS3), and the NF-κB pathway in IR-induced metastasis.
Main Methods:
- Investigated the interaction between MIF and rpS3 in NSCLC cell lines (A549, NCI-H358) under unirradiated and irradiated conditions.
- Assessed NF-κB pathway activation, pro-inflammatory cytokine secretion, and epithelial-mesenchymal transition (EMT) marker expression post-IR.
- Utilized in vivo xenograft models to confirm the impact of MIF-rpS3 complex dissociation on tumor metastasis.
Main Results:
- IR induced dissociation of the MIF-rpS3 complex in NSCLC cells.
- Dissociation activated the NF-κB pathway, leading to transactivation of target genes and increased secretion of pro-inflammatory cytokines.
- IR-induced dissociation modulated EMT markers and promoted tumor metastasis in vivo.
Conclusions:
- Dissociation of the MIF-rpS3 complex is a critical event following IR exposure in NSCLC.
- This dissociation activates the NF-κB pathway, driving IR-induced metastatic conversion of NSCLC.
- Targeting the MIF-rpS3 complex or NF-κB pathway may offer strategies to inhibit radiation-induced metastasis in NSCLC.
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