Priority Research Paper Volume 14, Issue 3 pp 1068—1086

Senescence-associated tumor growth is promoted by 12-Lipoxygenase

Shilpa Patil1, , Jessica L. Reedy1, , Bradley T. Scroggins1, , Ayla O. White1, , Seokjoo Kwon1, , Uma Shankavaram1, , Alfonso López-Coral1, , Eun Joo Chung1, , Deborah E. Citrin1, ,

  • 1 Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

Received: October 20, 2021       Accepted: February 8, 2022       Published: February 14, 2022
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Copyright: © 2022 Patil et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Radiation therapy is a commonly used treatment modality for cancer. Although effective in providing local tumor control, radiation causes oxidative stress, inflammation, immunomodulatory and mitogenic cytokine production, extracellular matrix production, and premature senescence in lung parenchyma. The senescence associated secretory phenotype (SASP) can promote inflammation and stimulate alterations in the surrounding tissue. Therefore, we hypothesized that radiation-induced senescent parenchymal cells in irradiated lung would enhance tumor growth. Using a murine syngeneic tumor model of melanoma and non-small cell lung cancer lung metastasis, we demonstrate that radiation causes a significant increase in markers of premature senescence in lung parenchyma within 4 to 8 weeks. Further, injection of B16F0 (melanoma) or Lewis Lung carcinoma (epidermoid lung cancer) cells at these time points after radiation results in an increase in the number and size of pulmonary tumor nodules relative to unirradiated mice. Treatment of irradiated mice with a senolytic agent (ABT-737) or agents that prevent senescence (rapamycin, INK-128) was sufficient to reduce radiation-induced lung parenchymal senescence and to mitigate radiation-enhanced tumor growth. These agents abrogated radiation-induced expression of 12-Lipoxygenase (12-LOX), a molecule implicated in several deleterious effects of senescence. Deficiency of 12-LOX prevented radiation-enhanced tumor growth. Together, these data demonstrate the pro-tumorigenic role of radiation-induced senescence, introduces the dual TORC inhibitor INK-128 as an effective agent for prevention of radiation-induced normal tissue senescence, and identifies senescence-associated 12-LOX activity as an important component of the pro-tumorigenic irradiated tissue microenvironment. These studies suggest that combining senotherapeutic agents with radiotherapy may decrease post-therapy tumor growth.


SASP: senescence associated secretory phenotype; IR: irradiation; SA-β-galactosidase: senescence associated β-galactosidase; ALOX12: Arachidonate 12-Lipoxygenase gene; 12-LOX: 12-lipoxygenase protein; 12(S)-HpETE: 12S-hydroperoxy-5Z, 8Z, 10E, 14Z, eicosatetraenoic acid; 12(S)-HETE: 12S-hydroxy-5Z, 8Z 10E, 14Z eicosatetraenoic acid; p38: p38 mitogen-activated kinases; JNK: c-Jun N-terminal kinase.