リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

大学・研究所にある論文を検索できる 「Cryptotanshinone suppresses tumorigenesis by inhibiting lipogenesis and promoting reactive oxygen species production in KRAS‑activated pancreatic cancer cells」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。
リケラボ

コピーが完了しました

URLをコピーしました

論文の公開元へ論文の公開元へ
書き出し

Cryptotanshinone suppresses tumorigenesis by inhibiting lipogenesis and promoting reactive oxygen species production in KRAS‑activated pancreatic cancer cells

TERADO Tokio KIM Chul Jang 10204968 USHIO Akiyo MINAMI Kahori TAMBE Yukihiro 50283560 KAGEYAMA Susumu 50378452 0000-0001-7150-647X KAWAUCHI Akihiro 90240952 TSUNODA Toshiyuki SHIRASAWA Senji TANAKA Hiroyuki 10293820 INOUE Hirokazu 30176440 滋賀医科大学

2022.07.26

概要

Pyruvate dehydrogenase kinase 4 (PDK4) is an important regulator of energy metabolism. Previously, knockdown of PDK4 by specific small interfering RNAs (siRNAs) have been shown to suppress the expression of Κirsten rat sarcoma viral oncogene homolog (KRAS) and the growth of lung and colorectal cancer cells, indicating that PDK4 is an attractive target of cancer therapy by altering energy metabolism. The authors previously reported that a novel small molecule, cryptotanshinone (CPT), which inhibits PDK4 activity, suppresses the in vitro three‑dimensional (3D)‑spheroid formation and in vivo tumorigenesis of KRAS‑activated human pancreatic and colorectal cancer cells. The present study investigated the molecular mechanism of CPT‑induced tumor suppression via alteration of glutamine and lipid metabolism in human pancreatic and colon cancer cell lines with mutant and wild‑type KRAS. The antitumor effect of CPT was more pronounced in the cancer cells containing mutant KRAS compared with those containing wild‑type KRAS. CPT treatment decreased glutamine and lipid metabolism, affected redox regulation and increased reactive oxygen species (ROS) production in the pancreatic cancer cell line MIAPaCa‑2 containing mutant KRAS. Suppression of activated KRAS by specific siRNAs decreased 3D‑spheroid formation, the expression of acetyl‑CoA carboxylase 1 and fatty acid synthase (FASN) and lipid synthesis. The suppression also reduced glutathione‑SH/glutathione disulfide and increased the production of ROS. Knockdown of FASN suppressed lipid synthesis in MIAPaCa‑2 cells, partially promoted ROS production and mildly suppressed 3D‑spheroid formation. These results indicated that CPT reduced tumorigenesis by inhibiting lipid metabolism and promoting ROS production in a mutant KRAS‑dependent manner. This PDK4 inhibitor could serve as a novel therapeutic drug for KRAS‑driven intractable cancers via alteration of cell metabolism.

論文の公開元へ

この論文で使われている画像

関連論文

関連論文をもっと見る

参考文献

1. Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell 144: 646‑674, 2011.

2. Hsu PP and Sabatini DM: Cancer cell metabolism: Warburg and beyond. Cell 134: 703‑707, 2008.

3. Vander Heiden MG, Cantley LC and Thompson CB: Understanding the warburg effect: The metabolic requirements of cell proliferation. Science 324: 1029‑1033, 2009.

4. Sugden MC and Holness MJ: Mechanisms underlying regulation of the expression and activities of the mammalian pyruvate dehy‑ drogenase kinases. Arch Physiol Biochem 112: 139‑149, 2006.

5. Tambe Y, Hasebe M, Kim CJ, Yamamoto A and Inoue H: The drs tumor suppressor regulates glucose metabolism via lactate dehydrogenase‑B. Mol Carcinog 55: 52‑63, 2016.

6. Kinnaird A, Dromparis P, Saleme B, Gurtu V, Watson K, Paulin R, Zervopoulos S, Stenson T, Sutendra G, Pink DB, et al: Metabolic modulation of clear‑cell renal cell carcinoma with dichloroacetate, an inhibitor of pyruvate dehydrogenase kinase. Eur Urol 69: 734‑744, 2016.

7. Saunier E, Benelli C and Bortoli S: The pyruvate dehydrogenase complex in cancer: An old metabolic gatekeeper regulated by new pathways and pharmacological agents. Int J Cancer 138: 809‑817, 2016.

8. Leclerc D, Pham DN, Lévesque N, Truongcao M, Foulkes WD, Sapienza C and Rozen R: Oncogenic role of PDK4 in human colon cancer cells. Br J Cancer 116: 930‑936, 2017.

9. Trinidad AG, Whalley N, Rowlinson R, Delpuech O, Dudley P, Rooney C and Critchlow SE: Pyruvate dehydrogenase kinase 4 exhibits a novel role in the activation of mutant KRAS, regulating cell growth in lung and colorectal tumour cells. Oncogene 36: 6164‑6176, 2017.

10. Stacpoole PW: Therapeutic targeting of the pyruvate dehydroge‑ nase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis in cancer. J Natl Cancer Inst: 109, 2017.

11. Sutendra G and Michelakis ED: Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology. Front Oncol 3: 38, 2013.

12. Qin C, Yang G, Yang J, Ren B, Wang H, Chen G, Zhao F, You L, Wang W and Zhao Y: Metabolism of pancreatic cancer: Paving the way to better anticancer strategies. Mol Cancer 19: 50, 2020.

13. Faubert B, Solmonson A and DeBerardinis RJ: Metabolic repro‑ gramming and cancer progression. Science 368: eeaw5473, 2020.

14. Chen M and Hang J: The expanded role of fatty acid metabolism in cancer: New aspects and targets. Precis Clin Med 2: 183‑191, 2019.

15. Wang W, Bai L, Li W and Cui J: The lipid metabolic landscape of cancers and new therapeutic perspectives. Front Oncol 10: 605154, 2020.

16. Mustachio LM, Chelariu‑Raicu A, Szekvolgyi L and Roszik J: Targeting KRAS in cancer: Promising therapeutic strategies. Cancers (Basel) 13: 1024. 2021.

17. Han CW, Jeong MS and Jang SB: Understand KRAS and the quest for anti‑cancer drugs. Cells 10: 842, 2021.

18. Kaek SA, Papagiannakopoulos T, Shah YM and Lyssiotis CA: Metabolic networks in mutant KRAS‑driven tumours: Tissue specificities and the microenvironment. Nat Rev Cancer 21: 510‑525, 2021.

19. Muyinda IJ, Park JG, Jang EJ and Yoo BC: KRAS, A prime mediator in pancreatic lipid synthesis through extra mitochondrial glutamine and citrate metabolism. Int J Mol Sci 22: 5070, 2021.

20. Tambe Y, Terado T, Kim CJ, Mukaisho K, Yoshida S, Sugihara H, Tanaka H, Chida J, Kido H, Yamaji K, et al: Antitumor activity of potent pyruvate dehydrogenase kinase 4 inhibitors from plants in pancreatic cancer. Mol Carcinog 58: 1726‑1737, 2019.

21. Shirasawa S, Furuse M, Yokoyama A and Sasazuki T: Altered growth of human colon cancer cell lines disrupted at activated Ki‑ras. Science 260: 85‑88, 1993.

22. Chang L, Fang S, Chen Y, Yang Z, Yuan Y, Zhang J, Ye L and Gu W: Inhibition of FASN suppresses the malignant biological behavior of non‑small cell lung cancer cells via deregulating glucose metabolism and AKT/ERK pathway. Lipids Health Dis 18: 118, 2019.

23. Pecot CV, Wu SY, Bellister S, Filant J, Rupaimoole R, Hisamatsu T, Bhattacharya R, Maharaj A, Azam S, Rodriguez‑Aguayo C, et al: Therapeutic silencing of KRAS using systemically delivered siRNAs. Mol Cancer Ther 13: 2876‑2885, 2014.

24. Hayes JD, Dinkova‑Kostova AT and Tew KD: Oxidative stress in cancer. Cancer Cell 38: 167‑197, 2020.

25. Sang‑Min J, Navdeep SC and Nissim H: AMPK regulates NADPH homeostasiss to promote tumour cell survival during energy stress. Nature 485: 661‑665, 2012.

26. Bueno MJ and Quintela‑Fandino M: Emerging role of fatty acid synthase in tumor initiation: Implications for cancer prevention. Mol Cell Oncol 7: e1709389, 2020.

27. Molenaar RJ, Maciejewski JP, Wilmink JW and van Noorden CJ: Wild‑type and mutated IDH1/2 enzymes and therapy responses. Oncogene 37: 1949‑1960, 2018.

28. Kim CJ, Terado T, Tambe Y, Mukaisho K, Kageyama S, Kawauchi A and Inoue H: Cryptotanshinone, a novel PDK4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis. Int J Oncol 59: 40, 2021.

参考文献をもっと見る

全国の大学の
卒論・修論・学位論文
を
一発検索！

この論文の関連論文を見る