| First Author | Koerner L | Year | 2023 |
| Journal | Cell Death Differ | Volume | 30 |
| Issue | 4 | Pages | 938-951 |
| PubMed ID | 36653597 | Mgi Jnum | J:334555 |
| Mgi Id | MGI:7460998 | Doi | 10.1038/s41418-023-01112-5 |
| Citation | Koerner L, et al. (2023) NEMO- and RelA-dependent NF-kappaB signaling promotes small cell lung cancer. Cell Death Differ 30(4):938-951 |
| abstractText | Small cell lung cancer (SCLC) is an aggressive type of lung cancer driven by combined loss of the tumor suppressors RB1 and TP53. SCLC is highly metastatic and despite good initial response to chemotherapy patients usually relapse, resulting in poor survival. Therefore, better understanding of the mechanisms driving SCLC pathogenesis is required to identify new therapeutic targets. Here we identified a critical role of the IKK/NF-kappaB signaling pathway in SCLC development. Using a relevant mouse model of SCLC, we found that ablation of NEMO/IKKgamma, the regulatory subunit of the IKK complex that is essential for activation of canonical NF-kappaB signaling, strongly delayed the onset and growth of SCLC resulting in considerably prolonged survival. In addition, ablation of the main NF-kappaB family member p65/RelA also delayed the onset and growth of SCLC and prolonged survival, albeit to a lesser extent than NEMO. Interestingly, constitutive activation of IKK/NF-kappaB signaling within the tumor cells did not exacerbate the pathogenesis of SCLC, suggesting that endogenous NF-kappaB levels are sufficient to fully support tumor development. Moreover, TNFR1 deficiency did not affect the development of SCLC, showing that TNF signaling does not play an important role in this tumor type. Taken together, our results revealed that IKK/NF-kappaB signaling plays an important role in promoting SCLC, identifying the IKK/NF-kappaB pathway as a promising therapeutic target. |
