The Impact of Nrf2 Silencing on Nrf2-PD-L1 Axis to Overcome Oxaliplatin Resistance  and Migration in Colon Cancer Cells

Payandeh, Zahra; Tazehkand, Abbas Pirpour; Mansoori, Behzad; Khaze, Vahid; Asadi, Milad; Baradaran, Behzad; Samadi, Nasser

doi:10.18502/ajmb.v13i3.6371

Cited by 14 publications

(15 citation statements)

References 32 publications

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“…These features confirm the critical role of Nrf2 in the control of resistance in cancer cells in response to chemotherapeutic agents. In line with our results, Payandeh et al 29,30 33 In another study, Exo harboring ubiquitin carboxy-terminal hydrolase-L1-mediated adriamycin resistance in breast cancer cells. 34 Concerning drug resistance in CC, several different proteins have been identified.…”

Section: Discussionsupporting

confidence: 92%

In vitro exosomal transfer of Nrf2 led to the oxaliplatin resistance in human colorectal cancer LS174T cells

Mostafazadeh

Kahroba

Haiaty

et al. 2022

Cell Biochemistry & Function

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Chemotherapy resistance is a serious pitfall in the treatment of colon cancers (CCs).Previous studies have found that exosomes (Exo) play a pivotal role in tumor drug resistance via the transfer of proteins and genetic materials to the acceptor cells. To date, the mechanisms orchestrating Exo-derived resistance in cancer cells have been the center of attention. Herein, we aimed to evaluate the role of exosomal nuclear factor erythroid 2-related factor 2 (Nrf2) on oxaliplatin (1-OHP) resistance in human colorectal cancer LS174T cells in vitro. To this end, exosomal-Nrf2-mediated 1-OHP resistance was examined using different assays. Exo was isolated from resistant LS174T cells (LS174T/R) and added to the culture medium of sensitive LS174T cells (LS174T/S). According to our data, LS174T/S cells successfully adsorbed PKH26-Exo driven from LS174T/R cells. Western blotting showed an increased Nrf2 level in Exo isolated from LS174T/R cells compared to LS174T/S cell-derived Exo (p < .05). The incubation of LS174T/S cells with LS174T/ R-derived Exo increased half-maximal inhibitory concentration values in response to treatment with 1-OHP (p < .05). Besides this, the apoptotic changes were diminished in LS174T/S cells after incubation with LS174T/R-derived Exo. Of note, the exposure of LS174T/S cells to LS174T/R cell-derived Exo increased the expression of Nrf2 and P-glycoprotein (P-gp) compared to the nontreated LS174T/S cells (p < .05). In line with these changes, lower intracellular Rhodamin 123 content was detected in Exo-treated cells compared to the nontreated LS174T/S cells. Exo increased migration and clonogenic capacity of LS174T/S cells after incubation with Exo-derived from resistant cells. Of note, inhibition of Nrf2 with a specific blocker, brusatol, blunted these effects. Taken together, Exo-mediated transfer of Nrf2 is involved in the development of oxaliplatin resistance in CC cells by upregulating P-gp.

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Section: Discussionsupporting

confidence: 92%

In vitro exosomal transfer of Nrf2 led to the oxaliplatin resistance in human colorectal cancer LS174T cells

Mostafazadeh

Kahroba

Haiaty

et al. 2022

Cell Biochemistry & Function

Self Cite

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“…The management of colon cancer has been transformed by the development of ICIs. Nonetheless, aberrant upregulation of PD-L1 promotes chemoresistance and results in poor prognosis, while NRF2 inhibition remarkably lowers PD-L1 mRNA expression in sensitive and resistant cells [ 54 ].…”

Section: Nrf2mentioning

confidence: 99%

Current insight into the regulation of PD-L1 in cancer

Liu

et al. 2022

Exp Hematol Oncol

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The molecular mechanisms underlying cancer immune escape are a core topic in cancer immunology research. Cancer cells can escape T cell-mediated cellular cytotoxicity by exploiting the inhibitory programmed cell-death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1, CD274) immune checkpoint. Studying the PD-L1 regulatory pattern of tumor cells will help elucidate the molecular mechanisms of tumor immune evasion and improve cancer treatment. Recent studies have found that tumor cells regulate PD-L1 at the transcriptional, post-transcriptional, and post-translational levels and influence the anti-tumor immune response by regulating PD-L1. In this review, we focus on the regulation of PD-L1 in cancer cells and summarize the underlying mechanisms.

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“…Authors suggest that this effect is achieved by NRF2 activation of metabolic shift [ 197 ]. In support of this finding is the regulation of Programmed Death-Ligand 1 (PD-L1) by NRF2 in colon cancer tissues, where up-regulation of PD-L1 by NRF2 create axis for oxaliplatin resistance [ 198 ].…”

Section: Nrf2 and Cancer Resistance To Therapiesmentioning

confidence: 99%

“…In colon cancer, NRF2 overexpression correlated with stage and grade of tumor [ 199 ]. The resistance of colon cancer cells to oxaliplatin could be avoided by the inhibition of NRF2-PD-L1 axis [ 198 ]. Interestingly, the gemcitabine resistance of pancreatic cancer cells is supported by NRF2 signaling.…”

Section: Nrf2 and Cancer Resistance To Therapiesmentioning

confidence: 99%

Oxidative Stress and Cancer Heterogeneity Orchestrate NRF2 Roles Relevant for Therapy Response

et al. 2022

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Oxidative stress and its end-products, such as 4- hydroxynonenal (HNE), initiate activation of the Nuclear Factor Erythroid 2-Related Factor 2 (NRF2)/KEAP1 signaling pathway that plays a crucial role in the maintenance of cellular redox homeostasis. However, an involvement of 4-HNE and NRF2 in processes associated with the initiation of cancer, its progression, and response to therapy includes numerous, highly complex events. They occur through interactions between cancer and stromal cells. These events are dependent on many cell-type specific features. They start with the extent of NRF2 binding to its cytoplasmic repressor, KEAP1, and extend to the permissiveness of chromatin for transcription of ARE-containing genes that are NRF2 targets. This review will explore epigenetic molecular mechanisms of NRF2 transcription through the specific molecular anatomy of its promoter. It will explain the role of NRF2 in cancer stem cells, with respect to cancer therapy resistance. Additionally, it also discusses NRF2 involvement at the cross-roads of communication between tumor associated inflammatory and stromal cells, which is also an important factor involved in the response to therapy.

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The Impact of Nrf2 Silencing on Nrf2-PD-L1 Axis to Overcome Oxaliplatin Resistance and Migration in Colon Cancer Cells

Cited by 14 publications

References 32 publications

In vitro exosomal transfer of Nrf2 led to the oxaliplatin resistance in human colorectal cancer LS174T cells

In vitro exosomal transfer of Nrf2 led to the oxaliplatin resistance in human colorectal cancer LS174T cells

Current insight into the regulation of PD-L1 in cancer

Oxidative Stress and Cancer Heterogeneity Orchestrate NRF2 Roles Relevant for Therapy Response

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