Doxorubicin resistance induces IL6 activation in the colon cancer cell line LS180

Abstract

Despite improvements in the development of drugs for the treatment of cancer, drug resistance remains a major obstacle. In colon cancer, following an initially promising response, patients develop drug resistance, which impacts the efficacy and halts the response of cancerous cells towards drugs. In the present study, a phosphatase and tensin homolog (PTEN) knockdown model of LS180 cells, doxorubicin-resistant models of LS180 cells as well as doxorubicin-resistant LS180 (PTEN) knockdown model were established. The present study demonstrated that doxorubicin resistance led to the activation of interleukin (IL)6 signalling pathway which was enhanced by knockdown of PTEN. There was also an increase in the levels of IL8 and IL2 which were further enchanced by knockdown of PTEN. Doxorubicin resistance also led to an increase in the population of cancer stem cells in LS180 and shPTEN-treated LS180 cells. Notably, doxorubicin resistance also induced epithelial to mesenchymal transition and increased the formation of mammospheres. Furthermore, the present study also reported that IL6 receptor antibody not only decreased IL6 levels but also led to a significant decreased number of cancer stem cell like population and mammosphere formation. In conclusion, in the present study it was demonstrated that doxorubicin resistance led to activation of IL6 signalling pathway which was further elevated by the knockdown of PTEN in the colon cancer cell line LS180. Thus, inhibiting the IL6 loop may provide an alternative pathway to tackle doxorubicin resistance.

Thymoquinone upregulates miR‐125a‐5p, attenuates STAT3 activation, and potentiates doxorubicin antitumor activity in murine solid Ehrlich carcinoma

“…[116] However, targeted inhibition of IL-6 signaling can suppress renal cancer cell proliferation and enhance their sensitivity to DOX through decreasing STAT3 phosphorylation. [127] Likewise, the current study revealed that DOX-induced increment of tumoral IL-6 content and STAT3 phosphorylation was attenuated by concomitant administration of TQ.…”

Revisiting IL-6 expression in the tumor microenvironment of classical Hodgkin lymphoma

“…2 The differences in the survival analysis outcome could be the moderate size of patient samples in both studies and lack of long-term followup time in Reynolds et al 2 Moreover, in Reynolds et al, 2 the study subjects received outdated treatment regimens not used in modern clinical settings. Because IL-6 can induce chemoresistance for multiple drugs, [10][11][12][13][14][15] their study could miss any indirect therapeuticresistance mechanism of IL-6 in the TME for patients treated with ABVD/BEACOPP. 2,59 Most patients in our study were treated with what are still considered to be contemporary first-line therapies, for example, ABVD and BEACOPP.…”

“…1,7,60 These pathways induce upregulation of several genes that promote tumor progression 1,7,60 and chemotherapy resistance. [10][11][12][13][14][15] The interest in IL-6 derived from nonmalignant cells in the TME has recently increased. One report showed that IL-6 produced by cancer-associated fibroblasts in prostate cancer inhibits doxorubicin-induced cell death.…”

“…6,7 Intracellular IL-6 can promote treatment resistance for programmed death 1 (PD-1) inhibition in cancer cells 8,9 and chemotherapy resistance for multiple drugs including doxorubicin and vinblastine, which are used in the treatment of cHL. [10][11][12][13][14][15] Reports show that elevated serum IL-6 is associated with adverse clinical parameters like advanced disease in cHL. [16][17][18] However, the source of serum IL-6 in cHL and its correlation to immune markers in the TME is unknown.…”