Inhibition of the RBMS1/PRNP axis improves ferroptosis resistance-mediated oxaliplatin chemoresistance in colorectal cancer
Yini Xu
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Tianjin General Surgery Institute, Tianjin, China
Search for more papers by this authorJingpeng Hao
Department of Anorectal Surgery, Tianjin Medical University Second Hospital, Tianjin, China
Search for more papers by this authorQiang Chen
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Tianjin General Surgery Institute, Tianjin, China
Search for more papers by this authorYafei Qin
Department of Vascular Surgery, Henan Provincial People's Hospital, The Affiliated People's Hospital of Zhengzhou University, Zhengzhou, China
Search for more papers by this authorHong Qin
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Tianjin General Surgery Institute, Tianjin, China
Search for more papers by this authorShaohua Ren
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Tianjin General Surgery Institute, Tianjin, China
Search for more papers by this authorChenglu Sun
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Tianjin General Surgery Institute, Tianjin, China
Search for more papers by this authorYanglin Zhu
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Tianjin General Surgery Institute, Tianjin, China
Search for more papers by this authorBo Shao
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Tianjin General Surgery Institute, Tianjin, China
Search for more papers by this authorJingyi Zhang
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Tianjin General Surgery Institute, Tianjin, China
Search for more papers by this authorCorresponding Author
Hao Wang
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Tianjin General Surgery Institute, Tianjin, China
Correspondence Hao Wang, Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Rd, Heping District, Tianjin 300052, China.
Email: [email protected] and [email protected]
Search for more papers by this authorYini Xu
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Tianjin General Surgery Institute, Tianjin, China
Search for more papers by this authorJingpeng Hao
Department of Anorectal Surgery, Tianjin Medical University Second Hospital, Tianjin, China
Search for more papers by this authorQiang Chen
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Tianjin General Surgery Institute, Tianjin, China
Search for more papers by this authorYafei Qin
Department of Vascular Surgery, Henan Provincial People's Hospital, The Affiliated People's Hospital of Zhengzhou University, Zhengzhou, China
Search for more papers by this authorHong Qin
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Tianjin General Surgery Institute, Tianjin, China
Search for more papers by this authorShaohua Ren
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Tianjin General Surgery Institute, Tianjin, China
Search for more papers by this authorChenglu Sun
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Tianjin General Surgery Institute, Tianjin, China
Search for more papers by this authorYanglin Zhu
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Tianjin General Surgery Institute, Tianjin, China
Search for more papers by this authorBo Shao
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Tianjin General Surgery Institute, Tianjin, China
Search for more papers by this authorJingyi Zhang
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Tianjin General Surgery Institute, Tianjin, China
Search for more papers by this authorCorresponding Author
Hao Wang
Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
Tianjin General Surgery Institute, Tianjin, China
Correspondence Hao Wang, Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Rd, Heping District, Tianjin 300052, China.
Email: [email protected] and [email protected]
Search for more papers by this authorYini Xu, Jingpeng Hao, and Qiang Chen contributed equally to this work.
Abstract
The majority of patients with advanced colorectal cancer have chemoresistance to oxaliplatin, and studies on oxaliplatin resistance are limited. Our research showed that RNA-binding motif single-stranded interacting protein 1 (RBMS1) caused ferroptosis resistance in tumor cells, leading to oxaliplatin resistance. We employed bioinformatics to evaluate publically accessible data sets and discovered that RBMS1 was significantly upregulated in oxaliplatin-resistant colorectal cancer cells, in tandem with ferroptosis suppression. In vivo and in vitro studies revealed that inhibiting RBMS1 expression caused ferroptosis in colorectal cancer cells, restoring tumor cell sensitivity to oxaliplatin. Mechanistically, this is due to RBMS1 inducing prion protein translation, resulting in ferroptosis resistance in tumor cells. Validation of clinical specimens revealed that RBMS1 is similarly linked to tumor development and a poor prognosis. Overall, RBMS1 is a potential therapeutic target with clinical translational potential, particularly for oxaliplatin chemoresistance in colorectal cancer.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data sets referenced to support the conclusions of this research are included in the article and its Supporting Information files.
Supporting Information
| Filename | Description |
|---|---|
| mc23647-sup-0001-Supplementary_Figure_1.docx2.1 MB | Supporting Information. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Miller KD, Nogueira L, Devasia T, et al. Cancer treatment and survivorship statistics, 2022. CA Cancer J Clin. 2022; 72: 409-436.
- 2Benson AB, Venook AP, Al-Hawary MM, et al. NCCN guidelines insights: colon cancer, version 2.2018. J Natl Comp Cancer Netw. 2018; 16: 359-369.
- 3Benson AB, Venook AP, Al-Hawary MM, et al. Rectal cancer, version 2.2018, NCCN clinical practice guidelines in oncology. J Natl Com Cancer Netw. 2018; 16: 874-901.
- 4Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014; 64: 104-117.
- 5Mao L, Li Y, Zhao J, et al. Transforming growth factor-β1 contributes to oxaliplatin resistance in colorectal cancer via epithelial to mesenchymal transition. Oncol Lett. 2017; 14: 647-654.
- 6Paquet-Fifield S, Koh SL, Cheng L, et al. Tight junction protein Claudin-2 promotes self-renewal of human colorectal cancer stem-like cells. Cancer Res. 2018; 78: 2925-2938.
- 7Jeught KV, Xu HC, Li YJ, Lu XB, Ji G. Drug resistance and new therapies in colorectal cancer. World J Gastroenterol. 2018; 24: 3834-3848.
- 8Wu QB, Sheng X, Zhang N, Yang MW, Wang F. Role of microRNAs in the resistance of colorectal cancer to chemoradiotherapy. Mol Clin Oncol. 2018; 8: 523-527.
- 9Giordano G, Remo A, Porras A, Pancione M. Immune resistance and EGFR antagonists in colorectal cancer. Cancers(Basel). 2019; 11(8). doi:10.3390/cancers11081089
- 10Cremolini C, Benelli M, Fontana E, et al. Benefit from anti-EGFRs in RAS and BRAF wild-type metastatic transverse colon cancer: a clinical and molecular proof of concept study. ESMO Open. 2019; 4:e000489.
- 11Sandhu J, Lavingia V, Fakih M. Systemic treatment for metastatic colorectal cancer in the era of precision medicine. J Surg Oncol. 2019; 119: 564-582.
- 12Sun J, Cheng X, Pan S, et al. Dichloroacetate attenuates the stemness of colorectal cancer cells via trigerring ferroptosis through sequestering iron in lysosomes. Environ Toxicol. 2021; 36: 520-529.
- 13Friedmann Angeli JP, Krysko DV, Conrad M. Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nat Rev Cancer. 2019; 19: 405-414.
- 14Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021; 22: 266-282.
- 15Liang C, Zhang X, Yang M, Dong X. Recent progress in ferroptosis inducers for cancer therapy. Adv Mater. 2019; 31:e1904197.
- 16Stockwell BR, Jiang X. The chemistry and biology of ferroptosis. Cell Chem Biol. 2020; 27: 365-375.
- 17Yamaguchi Y, Kasukabe T, Kumakura S. Piperlongumine rapidly induces the death of human pancreatic cancer cells mainly through the induction of ferroptosis. Int J Oncol. 2018; 52: 1011-1022.
- 18Ma S, Henson ES, Chen Y, Gibson SB. Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells. Cell Death Dis. 2016; 7:e2307.
- 19Hangauer MJ, Viswanathan VS, Ryan MJ, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017; 551: 247-250.
- 20Chen X, Kang R, Kroemer G, Tang D. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol. 2021; 18: 280-296.
- 21Tsoi J, Robert L, Paraiso K, et al. Multi-stage differentiation defines melanoma subtypes with differential vulnerability to drug-induced iron-dependent oxidative stress. Cancer Cell. 2018; 33: 890-904 e5.
- 22Viswanathan VS, Ryan MJ, Dhruv HD, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017; 547: 453-457.
- 23Li F, Zhao H, Su M, et al. HnRNP-F regulates EMT in bladder cancer by mediating the stabilization of Snail1 mRNA by binding to its 3′ UTR. EBioMedicine. 2019; 45: 208-219.
- 24Chen TM, Lai MC, Li YH, et al. hnRNPM induces translation switch under hypoxia to promote colon cancer development. EBioMedicine. 2019; 41: 299-309.
- 25Bisogno LS, Keene JD. RNA regulons in cancer and inflammation. Curr Opin Genet Dev. 2018; 48: 97-103.
- 26Boise LH, González-García M, Postema CE, et al. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell. 1993; 74: 597-608.
- 27Lv Y, Zhang W, Zhao J, et al. SRSF1 inhibits autophagy through regulating Bcl-x splicing and interacting with PIK3C3 in lung cancer. Signal Transduct Target Ther. 2021; 6: 108.
- 28Qi Y, Yu J, Han W, et al. A splicing isoform of TEAD4 attenuates the Hippo-YAP signalling to inhibit tumour proliferation. Nat Commun. 2016; 7:ncomms11840.
- 29Yu J, Navickas A, Asgharian H, et al. RBMS1 suppresses colon cancer metastasis through targeted stabilization of its mRNA regulon. Cancer Discov. 2020; 10: 1410-1423.
- 30Zhang W, Sun Y, Bai L, et al. RBMS1 regulates lung cancer ferroptosis through translational control of SLC7A11. J Clin Invest. 2021; 131:e152067.
- 31Carter H. Loss of RNA-binding protein RBMS1 promotes a metastatic transcriptional program in colorectal cancer. Cancer Discov. 2020; 10: 1261-1262.
- 32Liu M, Li H, Zhang H, et al. RBMS1 promotes gastric cancer metastasis through autocrine IL-6/JAK2/STAT3 signaling. Cell Death Dis. 2022; 13: 287.
- 33Zhang J, Zhang G, Zhang W, et al. Loss of RBMS1 promotes anti-tumor immunity through enabling PD-L1 checkpoint blockade in triple-negative breast cancer. Cell Death Differ. 2022; 29: 2247-2261.
- 34Zhou Y, Liang Z, Xia Y, et al. Disruption of RBMS3 suppresses PD-L1 and enhances antitumor immune activities and therapeutic effects of auranofin against triple-negative breast cancer. Chem Biol Interact. 2022; 369:110260.
- 35Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012; 149: 1060-1072.
- 36Hu K, Zhang X, Zhou L, Li J. Downregulated PRNP facilitates cell proliferation and invasion and has effect on the immune regulation in ovarian cancer. J Immunol Res. 2022; 2022: 1-11.
- 37Ye Z, Zhuo Q, Hu Q, et al. FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells. Redox Biol. 2021; 38:101807.
- 38Zhao Y, Li M, Yao X, et al. HCAR1/MCT1 regulates tumor ferroptosis through the lactate-mediated AMPK-SCD1 activity and its therapeutic implications. Cell Rep. 2020; 33:108487.
- 39Wan C, Sun Y, Tian Y, et al. Irradiated tumor cell-derived microparticles mediate tumor eradication via cell killing and immune reprogramming. Sci Adv. 2020; 6:eaay9789.
- 40Brown CW, Chhoy P, Mukhopadhyay D, Karner ER, Mercurio AM. Targeting prominin2 transcription to overcome ferroptosis resistance in cancer. EMBO Mol Med. 2021; 13:e13792.
- 41Zhao L, Peng Y, He S, et al. Apatinib induced ferroptosis by lipid peroxidation in gastric cancer. Gastric Cancer. 2021; 24: 642-654.
- 42Wang Q, Guo Y, Wang W, et al. RNA binding protein DAZAP1 promotes HCC progression and regulates ferroptosis by interacting with SLC7A11 mRNA. Exp Cell Res. 2021; 399:112453.
- 43Zhang Z, Guo M, Li Y, et al. RNA-binding protein ZFP36/TTP protects against ferroptosis by regulating autophagy signaling pathway in hepatic stellate cells. Autophagy. 2020; 16: 1482-1505.
- 44Brown DR, Qin K, Herms JW, et al. The cellular prion protein binds copper in vivo. Nature. 1997; 390: 684-687.
- 45Gao Z, Peng M, Chen L, et al. Prion protein protects cancer cells against endoplasmic reticulum stress induced apoptosis. Virol Sin. 2019; 34: 222-234.
- 46Mouillet-Richard S, Ermonval M, Chebassier C, et al. Signal transduction through prion protein. Science. 2000; 289: 1925-1928.
- 47Atkinson CJ, Kawamata F, Liu C, et al. EGFR and prion protein promote signaling via FOXO3a-KLF5 resulting in clinical resistance to platinum agents in colorectal cancer. Mol Oncol. 2019; 13: 725-737.
- 48Déry MA, Jodoin J, Ursini-Siegel J, et al. Endoplasmic reticulum stress induces PRNP prion protein gene expression in breast cancer. Breast Cancer Res. 2013; 15: R22.
- 49Zhou L, Shang Y, Liu C, et al. Overexpression of PrPc, combined with MGr1-Ag/37LRP, is predictive of poor prognosis in gastric cancer. Int J Cancer. 2014; 135: 2329-2337.
- 50Wiegmans AP, Saunus JM, Ham S, et al. Secreted cellular prion protein binds doxorubicin and correlates with anthracycline resistance in breast cancer. JCI Insight. 2019; 5:e124092.
