Low ferroptosis score predicts chemotherapy responsiveness and immune‐activation in colorectal cancer

Lv, Yang; Feng, Qi Sheng; Zhang, Zhiyuan; Zheng, Peng; Zhu, Dexiang; Qi, Lin; Chen, Si-Min; Mao, Yihao; Xu, Yu; Ji, Meiling; Xu, Jianmin; He, Guodong

doi:10.1002/cam4.4956

Cited by 12 publications

(11 citation statements)

References 45 publications

(71 reference statements)

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“…Given that APOL3 is a member of the APOL family, we first compared the clinical relationship between all APOL proteins and the ferroptosis score 13 . As shown in Figure 1A, APOL3 expression was positively correlated with the ferroptosis score, with the highest Spearman R value in the APOL family.…”

Section: Resultsmentioning

confidence: 99%

Intratumor APOL3 delineates a distinctive immunogenic ferroptosis subset with prognosis prediction in colorectal cancer

Lv,

Zheng,

Mao

et al. 2023

Cancer Science

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With the essential role of lipid transporting signaling in cancer‐related immunity, apolipoprotein L3 (APOL3), a member of the apolipoprotein L gene family, demonstrated significant modulation ability in immunity. However, the expression profile and critical role of APOL3 in colorectal cancer (CRC) remain unclear. This study aimed to investigate the prognostic significance of APOL3 expression and its biological predictive value in CRC. The study enrolled multiple cohorts, consisting of 911 tumor microarray specimens of CRC patients from Zhongshan Hospital, 412 transcriptional data from The Cancer Genome Atlas, and 30 single‐cell RNA sequencing (scRNA‐seq) from internal and external CRC patients. APOL3 mRNA expression was directly acquired from public datasets, and APOL3 protein expression was detected using immunohistochemistry. Finally, the associations of APOL3 expression with clinical outcomes, immune context, and genomic and ferroptotic features were analyzed. Low APOL3 expression predicted poor prognosis and inferior responsiveness to 5‐fluorouracil‐based adjuvant chemotherapy (ACT) and targeted therapy. APOL3 fosters an immune‐active microenvironment characterized by the promotion of ferroptosis, downregulation of macrophages, and upregulation of CD8+ T cell infiltration. Moreover, the expression of APOL3 in CD8+ T cells is intrinsically linked to ferroptosis and immune activation in CRC. In summary, APOL3 serves as an independent prognosticator and predictive biomarker for immunogenic ferroptosis, ACT, and targeted therapy in CRC. Furthermore, the APOL3 signaling activator could be a novel agent alone or in combination with current therapeutic strategies for CRC.

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Section: Resultsmentioning

confidence: 99%

Intratumor APOL3 delineates a distinctive immunogenic ferroptosis subset with prognosis prediction in colorectal cancer

Lv,

Zheng,

Mao

et al. 2023

Cancer Science

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“…GPX-4 is a primary regulator suppressing ferroptosis and also reported as a potent prognostic factor in various malignancies, including CRC [ 29 , 30 , 31 , 32 , 33 ]. Therefore, GPX-4 inhibition is considered to be a promising pharmacological target.…”

Section: Discussionmentioning

confidence: 99%

Curcumin and Andrographis Exhibit Anti-Tumor Effects in Colorectal Cancer via Activation of Ferroptosis and Dual Suppression of Glutathione Peroxidase-4 and Ferroptosis Suppressor Protein-1

Miyazaki

Shimada

et al. 2023

Pharmaceuticals

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Colorectal cancer (CRC) is the leading cause of cancer-related deaths worldwide. The limitations of current chemotherapeutic drugs in CRC include their toxicity, side effects, and exorbitant costs. To assess these unmet needs in CRC treatment, several naturally occurring compounds, including curcumin and andrographis, have gained increasing attention due to their multi-targeted functionality and safety vs. conventional drugs. In the current study, we revealed that a combination of curcumin and andrographis exhibited superior anti-tumor effects by inhibiting cell proliferation, invasion, colony formation, and inducing apoptosis. Genome-wide transcriptomic expression profiling analysis revealed that curcumin and andrographis activated the ferroptosis pathway. Moreover, we confirmed the gene and protein expression of glutathione peroxidase 4 (GPX-4) and ferroptosis suppressor protein 1 (FSP-1), the two major negative regulators of ferroptosis, were downregulated by this combined treatment. With this regimen, we also observed that intracellular accumulation of reactive oxygen species and lipid peroxides were induced in CRC cells. These cell line findings were validated in patient-derived organoids. In conclusion, our study revealed that combined treatment with curcumin and andrographis exhibited anti-tumorigenic effects in CRC cells through activation of ferroptosis and by dual suppression of GPX-4 and FSP-1, which have significant potential implications for the adjunctive treatment of CRC patients.

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“…Our previous analysis demonstrated that ferroptosis (combining of GPX4, NOX1 and ACSL4) indicated tumor immune-activation in CRC [18]. Thus, we performed a three-phase screen to identify the potential molecule targets.…”

Section: Integrated Screen Identifies Apol3 As the Significant Modula...mentioning

confidence: 99%

“…A biologically plausible hypothesis is that ferroptotic cells communicate with immune cells through a set of signals, such as the "find me" and "eat me" signals produced during cell death [17]. Our previous evidence demonstrated that tumor ferroptosis status (consisting of GPX4, NOX1 and ACSL4) can reflect enhanced CD8+ T cell infiltration based on CRC specimen [18]. The key molecular pathways of how ferroptosis enhance CD8+ T cell infiltration still remain obscure.…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein L3 enhances CD8+ T cell antitumor immunity of colorectal cancer by promoting LDHA-mediated ferroptosis

Lv¹,

Tang²,

Xu³

et al. 2023

Int. J. Biol. Sci.

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Aim: Colorectal cancer (CRC) is the leading cause of cancer associated death worldwide and immune checkpoint blockade therapy only benefit a small set of CRC patients. Tumor ferroptosis of CRC reflected immune-activation in our previous findings. Understanding the mechanisms underlying how to bolster CD8+ T cells function through ferroptosis in CRC tumor microenvironment (TME) will greatly benefit cancer immunotherapy. Methods: Genes between ferroptosis and CD8+ T cell function in CRC were screened through Cox, WGCNA and differential expression analysis. Immunohistochemistry and Immunofluorescence analysis were performed. Co-immunoprecipitation were performed to determine protein-protein interaction, mRNA level was determined by qRT-PCR. RSL3 was used to induce ferroptosis, and ferroptosis levels were evaluated by measuring Transmission Electron Microscope analysis, MDA, Fe 2+ level and cell viability. Results: We screened APOL3 as the significant modulator for ferroptosis-related CD8+ infiltration in CRC. Next, by in vitro and in vivo, we found that increased APOL3 expression was positively correlated with sensitivity to ferroptosis and antitumor ability of CD8+ T cells. Next, we demonstrated that APOL3 can binds LDHA and promote its ubiquitylation-related degradation. Then, based on in vivo analysis and tumor specimen, we discovered the APOL3-LDHA axis can facilitate the tumor ferroptosis and cytotoxic ability of CD8+ T cells through increased IFNγ and decreased lactic acid concentration. Conclusion:The present study demonstrated that APOL3 promotes ferroptosis and immunotherapy in colorectal cancer cells. The present work provides us with a novel target to overcome drug resistance to ferroptosis and immunotherapy.

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Low ferroptosis score predicts chemotherapy responsiveness and immune‐activation in colorectal cancer

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 12 publications

References 45 publications

Intratumor APOL3 delineates a distinctive immunogenic ferroptosis subset with prognosis prediction in colorectal cancer

Intratumor APOL3 delineates a distinctive immunogenic ferroptosis subset with prognosis prediction in colorectal cancer

Curcumin and Andrographis Exhibit Anti-Tumor Effects in Colorectal Cancer via Activation of Ferroptosis and Dual Suppression of Glutathione Peroxidase-4 and Ferroptosis Suppressor Protein-1

Apolipoprotein L3 enhances CD8+ T cell antitumor immunity of colorectal cancer by promoting LDHA-mediated ferroptosis

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