The mechanisms by which chemotherapeutic drugs mediate efficacy and toxicity in patients across cancers are not fully understood. A poorly understood aspect of the tumor cell response to chemotherapy is cytokine regulation. Some drug-induced cytokines promote the anti-cancer activity of the drugs, but others may promote proliferation, metastasis, and drug resistance. We evaluated effects of clinical chemotherapeutics oxaliplatin, cisplatin, 5-fluorouracil (5-FU), doxorubicin, paclitaxel, docetaxel, and carboplatin on a panel of 52 cytokines in MCF7 breast cancer (BC) cells. We observed pan-drug effects, such as the upregulation of TRAIL-R2 and Chitinase 3-like 1 and drug-specific effects on interleukin and CXCL cytokines. We compared cytokine regulation in MCF7 BC and HCT116 colorectal cancer (CRC) cells, revealing tissue-specific drug effects such as enhanced upregulation of TRAIL-R2 and downregulation of IFN-β and TRAIL in MCF7 by cisplatin, oxaliplatin, and 5-FU. We found that chemotherapy-inducible transcripts have varying potential for prognostic significance in CRC versus BC. Among the non-prognostic CRC genes that were prognostic in BC were NFKBIA and GADD45A, both of which support anti-cancer drug mechanisms. Thus, we establish a novel 7-drug, 52-cytokine signature in MCF7 BC cells and a 3-drug, 40-cytokine signature in HCT116 CRC cells that suggest drug-specific and tissue-specific cytokine regulation. Distinct differences across prognostic gene signatures in BC and CRC further support tissue specificity in the relative impact of drug-regulated genes on patient survival.
Keywords: 5-fluorouracil; Breast cancer; carboplatin; cisplatin; colorectal cancer; cytokines; docetaxel; doxorubicin; oxaliplatin; paclitaxel.
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