Abstract
Elucidation of TNF-directed mechanisms for cell death induction and maintenance of tumor growth has revealed a role for receptor-interacting protein kinases 1 and 3 (RIPK1/RIP1 and RIPK3/RIP3), components of the necrosome complex, as determinants of cell fate. Here, the participation of TNF signaling was analyzed with regard to the cytotoxic action of different DNA-damaging agents in a panel of colon cancer cells. While most of these cell lines were insensitive to TNF, combination with these drugs increased sensitivity by inducing cell death and DNA damage, especially in the case of the topoisomerase inhibitor SN38. Changes in levels of RIP1 and RIP3 occurred following monotherapy with SN38 or in combination with TNF. Downregulation of RIP1 resulted in increased resistance to SN38, implying a requirement for RIP1 in mediating cytotoxicity through the TNF/TNFR signaling pathway. Downregulation of RIP1 in a xenograft model impaired tumor growth inhibition from SN38 treatment, suggesting the potential of RIP1 to determine the clinical outcome of irinotecan treatment. These results indicate that TNF plays a key role in determining the cytotoxic effectiveness of SN38 in colorectal cancer and suggests a re-evaluation of TNF-based interventions to enhance therapeutic efficacy.Implications: The capacity of RIP1 to influence drug sensitivity suggests RIP1 may have biomarker potential. Mol Cancer Res; 15(4); 395-404. ©2017 AACR.
Highlights
Responses to the DNA damage caused by 5-fluorouracil (5-FU), oxaliplatin, and irinotecan, the major chemotherapeutic agents for treatment of colorectal cancer [1,2,3], are believed to determine whether cell death or survival results
Focusing on SN38, with which the effects were most pronounced, we show that TNF increases the cytotoxicity of SN38 by inducing cell death in association with increased DNA damage
By using cell lines in which RIP1 and RIP3 expression has been downregulated, we show that RIP1, but not RIP3, plays a key role in this connection between DNA damage and cell death
Summary
Responses to the DNA damage caused by 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (the active metabolite of which is SN38), the major chemotherapeutic agents for treatment of colorectal cancer [1,2,3], are believed to determine whether cell death or survival results. The known responses to DNA-damaging agents include activation of DNA repair pathways, altered transcriptional programs, and modified interaction with the external environment, potentially to evoke compensatory responses [4]. These interactions include the production of biologically active peptides, as well as modification of plasma membrane receptors involved in growth and survival [5]. TNF emerged as a cytokine with a dual role, involved in both cell death and cell survival depending on the biologic context, and playing a key role in inflammation, an action that influenced the toxicity profile of systemically administered drug.
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