Caveolin-1 mediates the utilization of extracellular proteins for survival in refractory gastric cancer
2
조회
0
다운로드
0
인용
0
참고문헌
초록
Despite advances in cancer therapy, the clinical outcome of patients with gastric cancer remains poor, largely due to tumor heterogeneity. Thus, finding a hidden vulnerability of clinically refractory subtypes of gastric cancer is crucial. Here, we report that chemoresistant gastric cancer cells rely heavily on endocytosis, facilitated by caveolin-1, for survival. caveolin-1 was highly upregulated in the most malignant stem-like/EMT/mesenchymal (SEM)-type gastric cancer cells, allowing caveolin-1-mediated endocytosis and utilization of extracellular proteins via lysosomal degradation. Downregulation of caveolin-1 alone was sufficient to induce cell death in SEM-type gastric cancer cells, emphasizing its importance as a survival mechanism. Consistently, chloroquine, a lysosomal inhibitor, successfully blocked caveolin-1-mediated endocytosis, leading to the marked suppression of tumor growth in chemorefractory gastric cancer cells in vitro, including patient-derived organoids, and in vivo. Together, our findings suggest that caveolin-1-mediated endocytosis is a key metabolic pathway for gastric cancer survival and a potential therapeutic target.
Abstract
Despite advances in cancer therapy, the clinical outcome of patients with gastric cancer remains poor, largely due to tumor heterogeneity. Thus, finding a hidden vulnerability of clinically refractory subtypes of gastric cancer is crucial. Here, we report that chemoresistant gastric cancer cells rely heavily on endocytosis, facilitated by caveolin-1, for survival. caveolin-1 was highly upregulated in the most malignant stem-like/EMT/mesenchymal (SEM)-type gastric cancer cells, allowing caveolin-1-mediated endocytosis and utilization of extracellular proteins via lysosomal degradation. Downregulation of caveolin-1 alone was sufficient to induce cell death in SEM-type gastric cancer cells, emphasizing its importance as a survival mechanism. Consistently, chloroquine, a lysosomal inhibitor, successfully blocked caveolin-1-mediated endocytosis, leading to the marked suppression of tumor growth in chemorefractory gastric cancer cells in vitro, including patient-derived organoids, and in vivo. Together, our findings suggest that caveolin-1-mediated endocytosis is a key metabolic pathway for gastric cancer survival and a potential therapeutic target.
참고문헌 (55)
- Cheong, J. H., "Predictive test for chemotherapy response in resectable gastric cancer : a multi-cohort, retrospective analysis", Lancet. Oncol, 19, pp.629~638 (2018)
- Lei, Z., "Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil", Gastroenterology, 145, pp.554~565 (2013)
- Kumari, S., "Endocytosis unplugged : multiple ways to enter the cell", Cell Res, 20, pp.256~275 (2010)
- Fennelly, C., "Lysosomal biology in cancer", Methods Mol. Biol, 1594, pp.293~308 (2017)
- Bonam, S. R., "Lysosomes as a therapeutic target", Nat. Rev. Drug Discov, 18, pp.923~948 (2019)
- Piao, S., "Targeting the lysosome in cancer", Ann. N. Y. Acad. Sci, 1371, pp.45~54 (2016)
- Gyparaki, M. T., "Lysosome : the cell’s ‘suicidal bag’ as a promising cancer target", Trends Mol. Med, 20, pp.239~241 (2014)
- Commisso, C., "Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells", Nature, 497, pp.633~637 (2013)
- Kim, S. M., "Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways", J. Clin. Invest, 126, pp.4088~4102 (2016)
- Palm, W., "The utilization of extracellular proteins as nutrients is suppressed by mTORC1", Cell, 162, pp.259~270 (2015)
- Kiss, A. L., "Endocytosis via caveolae : alternative pathway with distinct cellular compartments to avoid lysosomal degradation? J", Cell. Mol. Med, 13, pp.1228~1237 (2009)
- Chidlow, J. H. Jr, "Caveolae, caveolins, and cavins : complex control of cellular signalling and inflammation", Cardiovasc. Res, 86, pp.219~225 (2010)
- Suzuoki, M., "Impact of caveolin-1 expression on prognosis of pancreatic ductal adenocarcinoma", Br. J. Cancer, 87, pp.1140~1144 (2002)
- Huang, C., "A novel FoxM1-caveolin signaling pathway promotes pancreatic cancer invasion and metastasis", Cancer Res, 72, pp.655~665 (2012)
- Ho, C. C., "Up-regulated caveolin-1 accentuates the metastasis capability of lung adenocarcinoma by inducing filopodia formation", Am. J. Pathol, 161, pp.1647~1656 (2002)
- Zhan, P., "Expression of caveolin-1 is correlated with disease stage and survival in lung adenocarcinomas", Oncol. Rep, 27, pp.1072~1078 (2012)
- Yoo, S. H., "Expression of caveolin-1 is associated with poor prognosis of patients with squamous cell carcinoma of the lung", Lung Cancer, 42, pp.195~202 (2003)
- Ho, C. C., "Caveolin-1 expression is significantly associated with drug resistance and poor prognosis in advanced non-small cell lung cancer patients treated with gemcitabine-based chemotherapy", Lung Cancer, 59, pp.105~110 (2008)
- Wang, S., "Caveolin-1 inhibits breast cancer stem cells via c-Myc-mediated metabolic reprogramming", Cell Death Dis, 11, pp.450~ (2020)
- Burgermeister, E., "Caveats of caveolin-1 in cancer progression", Cancer Lett, 268, pp.187~201 (2008)
- Nwosu, Z. C., "Caveolin-1 in the regulation of cell metabolism : a cancer perspective", Mol. Cancer, 15, pp.71~ (2016)
- Bender, F. C., "Caveolin-1 levels are down-regulated in human colon tumors, and ectopic expression of caveolin-1 in colon carcinoma cell lines reduces cell tumorigenicity", Cancer Res, 60, pp.5870~5878 (2000)
- Wiechen, K., "Caveolin-1 Is down-regulated in human ovarian carcinoma and acts as a candidate tumor suppressor gene", Am. J. Pathol, 159, pp.1635~1643 (2001)
- Sloan, E. K., "Caveolin-1 inhibits breast cancer growth and metastasis", Oncogene, 23, pp.7893~7897 (2004)
- Delvecchio, R., "Chloroquine, an Endocytosis Blocking Agent, Inhibits Zika Virus Infection in Different Cell Models", Viruses (2016)[DOI]
- Hu, T. Y., "Insights from nanomedicine into chloroquine efficacy against COVID-19", Nat. Nanotechnol, 15, pp.247~249 (2020)
- Kim, E. L., "Chloroquine activates the p53 pathway and induces apoptosis in human glioma cells", Neuro Oncol, 12, pp.389~400 (2010)
- Yang, S., "Pancreatic cancers require autophagy for tumor growth", Genes Dev, 25, pp.717~729 (2011)
- Maclean, K. H., "Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis", J. Clin. Invest, 118, pp.79~88 (2008)
- Sotelo, J., "Adding chloroquine to conventional treatment for glioblastoma multiforme : a randomized, double-blind, placebo-controlled trial", Ann. Intern. Med, 144, pp.337~343 (2006)
- Rosenfeld, M. R., "A phase I", II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme, 2014, pp.10, 1359~1368
- Mahalingam, D., "Combined autophagy and HDAC inhibition : a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors", Autophagy, 10, pp.1403~1414 (2014)
- Bartfeld, S., "In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection", Gastroenterology, 148, pp.126~136 (2015)
- Kim, J., "Single-cell analysis of gastric pre-cancerous and cancer lesions reveals cell lineage diversity and intratumoral heterogeneity", npj Precis. Oncol, 6, pp.9~ (2022)
- Wang, L., "The role of CD44 and cancer stem cells", Methods Mol Biol, 1692, pp.31~42 (2018)
- Lee, J., "Selective cytotoxicity of the NAMPT inhibitor FK866 toward gastric cancer cells with markers of the epithelial-mesenchymal transition, due to loss of NAPRT", Gastroenterology, 155, pp.799~814 (2018)
- Simón, L., "Caveolin-1 function at the plasma membrane and in intracellular compartments in cancer", Cancer Metastasis Rev, 39, pp.435~453 (2020)
- Shi, Y., "Critical role of CAV1", caveolin-1 in cell stress responses in human breast cancer cells via modulation of lysosomal function and autophagy, 2015, pp.11, 769~784
- Luzio, J. P., "Lysosomes : fusion and function", Nat. Rev. Mol. Cell Biol, 8, pp.622~632 (2007)
- Rennick, J. J., "Key principles and methods for studying the endocytosis of biological and nanoparticle therapeutics", Nat. Nanotechnol, 16, pp.266~276 (2021)
- Kamphorst, J. J., "Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein", Cancer Res, 75, pp.544~553 (2015)
- Maekawa, M., "Sequential breakdown of 3-phosphorylated phosphoinositides is essential for the completion of macropinocytosis", Proc. National Acad. Sci. USA, 111, pp.E978~E987 (2014)
- Su, H., "Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis", Cancer Cell, 39, pp.678~693 (2021)
- Kang, X., "LIMK1 promotes peritoneal metastasis of gastric cancer and is a therapeutic target", Oncogene, 40, pp.3422~3433 (2021)
- Liu, H., "Whole-exome sequencing to identify somatic mutations in peritoneal metastatic gastric adenocarcinoma : A preliminary study", Oncotarget, 7, pp.43894~43906 (2016)
- Scheel, C., "Cancer stem cells and epithelial-mesenchymal transition : concepts and molecular links", Semin. Cancer Biol, 22, pp.396~403 (2012)
- Zhang, Y., "Targeting the Wnt", β-catenin signaling pathway in cancer, 2020, pp.13, 165~
- Huang, L., "Epithelial-mesenchymal transition in gastric cancer", Am. J. Transl. Res, 7, pp.2141~2158 (2015)
- Gao, Q., "Resveratrol inhibits the hedgehog signaling pathway and epithelial-mesenchymal transition and suppresses gastric cancer invasion and metastasis", Oncol. Lett, 9, pp.2381~2387 (2015)
- Thomas, S., "Src and caveolin-1 reciprocally regulate metastasis via a common downstream signaling pathway in bladder cancer", Cancer Res, 71, pp.832~841 (2011)
- Chatterjee, M., "Caveolae-mediated endocytosis is critical for albumin cellular uptake and response to albumin-bound chemotherapy", Cancer Res, 77, pp.5925~5937 (2017)
- Zhao, Y., "Caveolin-1 expression predicts efficacy of weekly nab-paclitaxel plus gemcitabine for metastatic breast cancer in the phase II clinical trial", BMC Cancer, 18, pp.1019~ (2018)
- Pavlova, N. N., "The emerging hallmarks of cancer metabolism", Cell Metab, 23, pp.27~47 (2016)
- Yim, W. W. -Y., "Lysosome biology in autophagy", Cell Discov, 6, pp.6~ (2020)
- Sandri, M., "Protein breakdown in muscle wasting : Role of autophagy-lysosome and ubiquitin-proteasome", Int. J. Biochem. Cell Biol, 45, pp.2121~2129 (2013)
