Kaempferol sensitizes cell proliferation inhibition in oxaliplatin-resistant colon cancer cells

다국어 초록 (Multilingual Abstract)

Resolution to chemoresistance is a major challengein patients with advanced-stage malignancies. Thus,identifi cation of action points and elucidation of molecularmechanisms for chemoresist human cancer are necessary toovercome this challenge. In this study, we provide importantevidence that kaempferol targeting RSKs might be a strategyto reduce the oxaliplatin-resistant colon cancer cells. Wefound that MAPK and PI3K-AKT signaling were increasedin oxaliplatin (Ox)-resistant HCT116 (HCT116-Ox R ) cellscompared to Ox-sensitive HCT116 (HCT116-Ox S ) cells.
Comparison of cell sensitivities using SP600125 (JNKinhibitor), SB206580 (p38 kinase inhibitor), or MK-2206(AKT inhibitor) revealed that cell proliferation inhibitionwas strongly observed in HT29 cells compared to that inHCT116 cells in both Ox S and Ox R cells. Interestingly,SP600125, SB206580, and MK-2206 treatment showedhigher cell proliferation inhibition in Ox S cells than that in Ox R cells in both HCT116 and HT29 cells, except followingtreatments with 10 μM of SP600125, and 30 μMof SB206580. In comparison to magnolin and aschantin,kaempferol showed the strongest inhibitory eff ect on cellproliferation in both HCT116 and HT29 cells. Importantly,HCT116- and HT29-Ox R cells showed higher sensitivitiesto cell proliferation inhibition than those of HCT116- andHT29-Ox S cells, resulting in the accumulation of cells atthe G 2 /M-phases of the cell cycle. Finally, we showed thatAP-1 transactivation activity was markedly decreased bykaempferol in HCT116- and HT29-Ox R cells compared tothe activity levels in HCT116- and HT29-Ox S cells. Takentogether, the results demonstrate that kaempferol-mediatedAP-1 inhibition might be an important signaling mechanismto resolve the chemoresistance of Ox-resistant colon cancercells.

참고문헌 (Reference)

1 Cho YY, "olecular Targeting of ERKs/RSK2 Signaling in Cancers" 23 : 4247-4258, 2017

2 Liu ZG, "c-Fos over-expression promotes radioresistance and predicts poor prognosis in malignant glioma" 7 : 65946-65956, 2016

3 Jin Kyung Seok, "Therapeutic regulation of the NLRP3 infl ammasome in chronic infl ammatory diseases" 대한약학회 44 (44): 16-35, 2021

4 Papadatos-Pastos D, "The role of the PI3K pathway in colorectal cancer" 94 : 18-30, 2015

5 Igor Vivanco, "The phosphatidylinositol 3-Kinase–AKT pathway in human cancer" Springer Science and Business Media LLC 2 (2): 489-501, 2002

6 Yumeng Wei, "The combination of curcumin and 5-fluorouracil in cancer therapy" 대한약학회 41 (41): 1-13, 2018

7 Ian A. Prior, "The Frequency of Ras Mutations in Cancer" American Association for Cancer Research (AACR) 80 (80): 2969-2974, 2020

8 Hadara Rubinfeld, "The ERK Cascade: A Prototype of MAPK Signaling" Springer Science and Business Media LLC 31 (31): 151-174, 2005

9 Richard G. Pestell, "The Cyclins and Cyclin-Dependent Kinase Inhibitors in Hormonal Regulation of Proliferation and Differentiation*" The Endocrine Society 20 (20): 501-534, 1999

10 Lee CJ, "Targeting of magnolin on ERKs inhibits Ras/ERKs/RSK2-signaling-mediated neoplastic cell transformation" 35 : 432-441, 2014

11 Roymans D, "Slegers H(2001)Phosphatidylinositol 3-kinases in tumor progression" 268 : 487-498, 2001

12 Zahra Koveitypour, "Signaling pathways involved in colorectal cancer progression" Springer Science and Business Media LLC 9 (9): 97-, 2019

13 Wei Sun, "Scutellarin resensitizes oxaliplatin-resistant colorectal cancer cells to oxaliplatin treatment through inhibition of PKM2" Elsevier BV 21 : 87-97, 2021

14 Cho YY, "Ribosomal S6 kinase 2 is a key regulator in tumor promoter induced cell transformation" 67 : 8104-8112, 2007

15 Lim HC, "Ribosomal S6 Kinase 2 (RSK2) maintains genomic stability by activating the Atm/p53-dependent DNA damage pathway" 8 : e74334-, 2013

16 Poulikos I. Poulikakos, "Resistance to MEK Inhibitors: Should We Co-Target Upstream?" American Association for the Advancement of Science (AAAS) 4 (4): 2011

17 Chappell WH, "Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health" 2 : 135-164, 2011

18 Barlow AD, "Rapamycin toxicity in MIN6 cells and rat and human islets is mediated by the inhibition of mTOR complex 2(mTORC2)" 55 : 1355-1365, 2012

19 Yoo SM, "RSK2-mediated ELK3 activation enhances cell transformation and breast cancer cell growth by regulation of c-fos promoter activity" 2019

20 Lee CJ, "RSK2-induced stress tolerance enhances cell survival signals mediated by inhibition of GSK3beta activity" 440 : 112-118, 2013

21 Cho YY, "RSK2 as a key regulator in human skin cancer" 33 : 2529-2537, 2012

22 조용연, "RSK2 and its binding partners in cell proliferation, transformation and cancer development" 대한약학회 40 (40): 291-303, 2017

23 Florian J. Sulzmaier, "RSK2 activity mediates glioblastoma invasiveness and is a potential target for new therapeutics" Impact Journals, LLC 7 (7): 79869-79884, 2016

24 Peng C, "Phosphorylation of caspase-8 (Thr-263) by ribosomal S6 kinase 2 (RSK2) mediates caspase-8 ubiquitination and stability" 286 : 6946-6954, 2011

25 Qiang Wang, "PIK3CA mutations confer resistance to first-line chemotherapy in colorectal cancer" Springer Science and Business Media LLC 9 (9): 739-, 2018

26 Li N, "Nobiletin sensitizes colorectal cancer cells to oxaliplatin by PI3K/Akt/MTOR pathway" 24 : 303-312, 2019

27 Goel G, "Molecular characterization and biomarker identifi cation in colorectal cancer: toward realization of the precision medicine dream" 1 : 5895-5908, 2018

28 Pearson G, "Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions" 22 : 153-183, 2001

29 정현욱, "Metabolism-mediated drug interaction potential of HS-23, a new herbal drug for the treatment of sepsis in human hepatocytes and liver microsomes" 대한약학회 38 (38): 171-177, 2015

30 Hye-Young Min, "Mechanisms of resistance to chemotherapy in non-small cell lung cancer" 대한약학회 44 (44): 146-164, 2021

31 Ji‐Hong Song, "Magnolin targeting of ERK1/2 inhibits cell proliferation and colony growth by induction of cellular senescence in ovarian cancer cells" Wiley 58 (58): 88-101, 2018

32 Lee CJ, "Kaempferol targeting on the fi broblast growth factor receptor 3-ribosomal S6 kinase 2 signaling axis prevents the development of rheumatoid arthritis" 9 : 401-, 2018

33 Longley DB, "Johnston PG(2005)Molecular mechanisms of drug resistance" 205 : 275-292, 2005

34 Chae SH, "Isolation and identifi cation of inhibitory compounds on TNF-alpha production from Magnolia fargesii" 21 : 67-69, 1998

35 Cullen PJ, "Integration of calcium and Ras signalling" 3 : 339-348, 2002

36 Bradbury CM, "Increased activator protein 1 activity as well as resistance to heat-induced radiosensitization, hydrogen peroxide, and cisplatin are inhibited by indomethacin in oxidative stress-resistant cells" 61 : 3486-3492, 20011

37 Ying-Wooi Wan, "Hybrid Models Identified a 12-Gene Signature for Lung Cancer Prognosis and Chemoresponse Prediction" Public Library of Science (PLoS) 5 (5): e12222-, 2010

38 Yoo SM, "Epimagnolin targeting on an active pocket of mammalian target of rapamycin suppressed cell transformation and colony growth of lung cancer cells" 58 : 1221-1233, 019

39 Cao P, "Enhancement of oxaliplatin-induced colon cancer cell apoptosis by alantolactone, a natural product inducer of ROS" 15 : 1676-1684, 2019

40 Sarah V. Holt, "Enhanced Apoptosis and Tumor Growth Suppression Elicited by Combination of MEK (Selumetinib) and mTOR Kinase Inhibitors (AZD8055)" American Association for Cancer Research (AACR) 72 (72): 1804-1813, 2012

41 Sally Temraz, "Dual Inhibition of MEK and PI3K Pathway in KRAS and BRAF Mutated Colorectal Cancers" MDPI AG 16 (16): 22976-22988, 2015

42 Colburn NH, "Dissociation of mitogenesis and late-stage promotion of tumor cell phenotype by phorbol esters: mitogen-resistant variants are sensitive to promotion" 78 : 6912-6916, 1981

43 Aksamitiene E, "Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways:a fi ne balance" 40 : 139-146, 2012

44 Cree IA, "Chemosensitivity and chemoresistance testing in ovarian cance" 21 : 39-43, 2009

45 Bose D, "Chemoresistant colorectal cancer cells and cancer stem cells mediate growth and survival of bystander cells" 105 : 1759-1767, 2011

46 Wilson TR, "Chemoresistance in solid tumours" 17 (17): x315-x324, 2006

47 Lee DW, "Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer" 123 : 3513-3523, 2017

48 Lee CJ, "Aschantin targeting on the kinase domain of mammalian target of rapamycin suppresses epidermal growth factor-induced neoplastic cell transformation" 36 : 1223-1234, 2015

49 M S DuPont, "Absorption of kaempferol from endive, a source of kaempferol-3-glucuronide, in humans" Springer Science and Business Media LLC 58 (58): 947-954, 2004

50 Chresta CM, "AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity" 70 : 288-298, 2010

51 Yuan Wang, "AP-1 confers resistance to anti-cancer therapy by activating XIAP" Impact Journals, LLC 9 (9): 14124-14137, 2018

52 Chen AY, "A review of the dietary fl avonoid, kaempferol on human health and cancer chemoprevention" 138 : 2099-2107, 2013

53 Cho YY, "A regulatory mechanism for RSK2 NH(2)-terminal kinase activity" 69 : 4398-4406, 2009