NOLC1 Suppresses Immuno-chemotherapy by Inhibiting p53-mediated Ferroptosis in Gastric Cancer
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Curated by eLife
eLife Assessment
Overall, this fundamental study identified a novel role of NOLC1 in regulating p53 nuclear transcriptional activity and p53-mediated ferroptosis in gastric cancer. The evidence supporting the conclusions is solid, although some new evidence is needed to make it more robust. The work will be of broad interest to cancer biologists and oncologists.
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Abstract
Gastric cancer (GC) is one of the most malignant cancers, and cisplatin (Cis)-based chemotherapy remains the main clinical treatment for GC. However, Cis resistance often occurs, largely limiting its therapeutic efficacy in tumors. Therefore, a better understanding of the drug resistance mechanism could reveal new approaches for improving GC treatment efficacy. Here, we define the integrative role of nucleolar and coiled-body phosphoprotein 1 (NOLC1), a molecular chaperone that is significantly upregulated in GC tissues and Cis-resistant GC cells. Knocking down NOLC1 increased GC sensitivity to Cis by regulating ferroptosis. Mechanistically, NOLC1 binds to the p53 DNA binding domain (DBD), decreasing p53 nuclear translocation stimulated by Cis and suppressing p53 transcriptional functions. Then, the p53-mediated ferroptosis is suppressed. Furthermore, the silence of NOLC1 promoted ferroptosis-induced immunogenic cell death (ICD) and reprogrammed the immunosuppressive tumor microenvironment, thereby increasing sensitivity to anti-programmed cell death-1 (PD-1) therapy plus Cis. The combination of anti-PD-1 plus Cis effectively inhibited GC growth without significant side effects. In summary, our findings reveal that targeting NOLC1 may be a novel therapeutic strategy for GC and may increase the efficacy of chemotherapy combined with immune checkpoint inhibitor (ICI) therapy.
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eLife Assessment
Overall, this fundamental study identified a novel role of NOLC1 in regulating p53 nuclear transcriptional activity and p53-mediated ferroptosis in gastric cancer. The evidence supporting the conclusions is solid, although some new evidence is needed to make it more robust. The work will be of broad interest to cancer biologists and oncologists.
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Reviewer #1 (Public review):
Summary:
In this manuscript, the authors identified that NOLC1 was upregulated in gastric cancer samples, which promoted cancer progression and cisplatin resistance. They further found that NOLC1 could bind to p53 and decrease its nuclear transcriptional activity, then inhibit p53-mediated ferroptosis. There are several major concerns regarding the conclusions.
Strengths:
This study identified that NOLC1 could bind to p53 and decrease its nuclear transcriptional activity, then inhibit p53-mediated ferroptosis in gastric cancer.
Weaknesses:
The major conclusions were not sufficiently supported by the results. The experiments were not conducted in a comprehensive manner.
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Reviewer #2 (Public review):
Summary:
Shengsheng Zhao et al. investigated the role of nucleolar and coiled-body phosphoprotein 1 (NOLC1) in relegating gastric cancer (GC) development and cisplatin-induced drug resistance in GC. They found a significant correlation between high NOLC1 expression and the poor prognosis of GC. Meanwhile, upregulation of NOLC1 was associated with cis-resistant GC. Experimentally, the authors demonstrate that knocking down NOLC1 increased GC sensitivity to Cis possibly by regulating ferroptosis. Mechanistically, they found NOLC1 suppressed ferroptosis by blocking the translocation of P53 from the cytoplasm to the nucleus and promoting its degradation. In addition, The authors also evaluated the effect of combinational treatment of anti-PD-1 and cisplatin in NOLC1 -knockdown tumor cells, revealing a potential …
Reviewer #2 (Public review):
Summary:
Shengsheng Zhao et al. investigated the role of nucleolar and coiled-body phosphoprotein 1 (NOLC1) in relegating gastric cancer (GC) development and cisplatin-induced drug resistance in GC. They found a significant correlation between high NOLC1 expression and the poor prognosis of GC. Meanwhile, upregulation of NOLC1 was associated with cis-resistant GC. Experimentally, the authors demonstrate that knocking down NOLC1 increased GC sensitivity to Cis possibly by regulating ferroptosis. Mechanistically, they found NOLC1 suppressed ferroptosis by blocking the translocation of P53 from the cytoplasm to the nucleus and promoting its degradation. In addition, The authors also evaluated the effect of combinational treatment of anti-PD-1 and cisplatin in NOLC1 -knockdown tumor cells, revealing a potential role of NOLC1 in the targeted therapy for GC.
Strengths:
Chemoresistance is considered a major reason causing failure of tumor treatment and death of cancer patients. This paper explored the role of NOLC1 in the regulation of Cis-mediated resistance, which involves a regulated cell death named ferroptosis. These findings provide more evidence highlighting the study of regulated cell death to overcome drug resistance in cancer treatment, which could give us more potential strategies or targets for combating cancer.
Weaknesses:
More evidence supporting the regulation of ferroptosis induced by Cisplatin by NOLC1 should be added. Particularly, the role of ferroptosis in the cisplatin-resistance should be verified and whether NOLC1 regulates ferroptosis induced by additional FINs should be explored. Besides, the experiments to verify the regulation of ferroptosis sensitivity by NOLC1 are sort of superficial. The role of MDM2/p53 in ferroptosis or cisplatin resistance mediated by NOLC1 should be further studied by genetic manipulation of p53, which is the key evidence to confirm its contribution to NOLC1 regulation of GC and relative cell death.
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Reviewer #3 (Public review):
Summary:
The authors have put forth a compelling argument that NOLC1 is indispensable for gastric cancer resistance in both in vivo and in vitro models. They have further elucidated that NOLC1 silencing augments cisplatin-induced ferroptosis in gastric cancer cells. The mechanistic underpinning of their findings suggests that NOLC1 modulates the p53 nuclear/plasma ratio by engaging with the p53 DNA Binding Domain, which in turn impedes p53-mediated transcriptional regulation of ferroptosis. Additionally, the authors have shown that NOLC1 knockdown triggers the release of ferroptosis-induced damage-associated molecular patterns (DAMPs), which activate the tumor microenvironment (TME) and enhance the efficacy of the anti-PD-1 and cisplatin combination therapy.
Strengths:
The manuscript presents a robust …
Reviewer #3 (Public review):
Summary:
The authors have put forth a compelling argument that NOLC1 is indispensable for gastric cancer resistance in both in vivo and in vitro models. They have further elucidated that NOLC1 silencing augments cisplatin-induced ferroptosis in gastric cancer cells. The mechanistic underpinning of their findings suggests that NOLC1 modulates the p53 nuclear/plasma ratio by engaging with the p53 DNA Binding Domain, which in turn impedes p53-mediated transcriptional regulation of ferroptosis. Additionally, the authors have shown that NOLC1 knockdown triggers the release of ferroptosis-induced damage-associated molecular patterns (DAMPs), which activate the tumor microenvironment (TME) and enhance the efficacy of the anti-PD-1 and cisplatin combination therapy.
Strengths:
The manuscript presents a robust dataset that substantiates the authors' conclusion. They have identified NOLC1 as a potential oncogene that confers resistance to immuno-chemotherapy in gastric cancer through the mediation of ferroptosis and subsequent TME reprogramming. This discovery positions NOLC1 as a promising therapeutic target for gastric cancer treatment. The authors have delineated a novel mechanistic pathway whereby NOLC1 suppresses p53 transcriptional functions by reducing its nuclear/plasma ratio, underscoring the significance of p53 nuclear levels in tumor suppression over total protein levels.
Weaknesses:
While the overall findings are commendable, there are specific areas that could benefit from further refinement. The authors have posited that NOLC1 suppresses p53-mediated ferroptosis; however, the mRNA levels of ferroptosis genes regulated by p53 have not been quantified, which is a critical gap in the current study. In Figure 4A, transmission electron microscopy (TEM) results are reported solely for the MGC-803 cell line. It would be beneficial to include TEM data for the MKN-45 cell line to strengthen the findings. The authors have proposed a link between NOLC1-mediated reduction in the p53 nuclear/plasma ratio and gastric cancer resistance, yet the correlation between this ratio and patient prognosis remains unexplored, which is a significant limitation in the context of clinical relevance.
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