Research ArticleExperimental Studies

Involvement of Corticotropin-releasing Hormone-related Peptides in Cellular Stress Caused by Anticancer Drugs in Colorectal Cancer

GO KUWATA, KEIICHI IKEDA and YOSHINOBU MANOME
Anticancer Research August 2020, 40 (8) 4505-4511; DOI: https://doi.org/10.21873/anticanres.14455

Abstract

Background/Aim: The expression of corticotropin-releasing hormone (CRH)-related peptides involved in stress response in colorectal cancer has been reported. We examined the involvement of CRH-related peptides in cellular stress caused by anticancer drugs in colorectal cancer. Materials and Methods: Changes in the expression levels of CRH-related peptides and their receptors in HCT116, DLD-1, and SW480 cell lines after fluorouracil (5-FU) loading were evaluated. Effects of the receptor antagonist against DNA synthesis disorder caused by 5-FU and SN-38 were evaluated using the 3H-labeled deoxyribonucleoside incorporation assay. Results: No changes in the mRNA expression levels of CRH-related peptides (UCN and UCN2) -and their receptors (CRHR1 and CRHR2) were observed. Addition of antagonists to cells with DNA synthesis disorder caused by 5-FU and SN-38 showed no differences in the incorporation of 3H-labeled deoxyribonucleoside. Conclusion: CRH-related peptides showed no effect on the stress response to anticancer drugs nor on DNA synthesis disorder in colorectal cancer.

Colorectal cancer is the third most fatal cancer worldwide, over 1.8 million new cases and 881,000 deaths are estimated to have occurred in 2018 (1). It has been reported that the median survival time (MST) of patients with metastatic colorectal cancer without chemotherapy is approximately 8 months (2). With the advancement of recent chemotherapy (including FOLFOX, FOLFIRI, and molecular targeted therapy), the MST has been significantly improved to 30 months (3-5); however, complete recovery remains a challenge.

The expression of corticotropin-releasing hormone (CRH)-related peptides and their receptors in various cancer types (6-17), including colorectal cancer (18-21), has been reported in recent years. CRH and CRH-related peptides are physiologically peptide hormones that play a role in various stress responses (22-25). CRH is secreted in the hypothalamus in response to numerous types of stress, causing various stress responses in the biological body through the hypothalamic–pituitary–adrenal axis (26). CRH-related peptides exhibit homologies in amino acid sequences with CRH. Three types of CRH-related peptides, urocortin (UCN), UCN2, and UCN3, are known (22). They are widely distributed in not only the central nervous system, but also peripheral tissues, and their involvement in various stress responses has been indicated. Additionally, two types of receptors for CRH and CRH-related peptides (CRHR1 and CRHR2) are known (22, 23). CRH and CRH-related peptides act as ligands that are involved in stress response through these receptors. CRH has a high affinity to CRHR1, activating the hypothalamus-pituitary-portal axis via CRHR1 located in the pituitary and contributing to an increase in adrenocorticotropic hormone and glucocorticoids. UCN has an affinity to both CRHR1 and CRHR2, while UCN2 and UCN3 have an affinity for CRHR2. These CRH-related peptides are involved in stress responses that are not mediated by the hypothalamus-pituitary-portal axis in the body, and are associated with cardioprotective action against stress-induced myocardial ischemia (27), stress-induced gastrointestinal motility disorders (28-30), and regulation of immune function (31).

It has been reported that these peptides and receptors may influence the proliferation, migration, and invasion potencies of cancer cells (18, 19, 32-35). However, different results have been shown and no consensus has yet been reached. Additionally, although it is possible that the physiological function of these CRH-related peptides may be in stress response to chemotherapy and modification of therapeutic effects of anticancer drugs, no such research on chemotherapy has been reported.

Figure 1.
Figure 1.

The quantitative reverse transcriptase-polymerase chain reaction values of basal urocortin (UCN), UCN2, UCN3 corticotropin-releasing hormone-related peptides receptors CRHR1, and CRHR2 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression at the mRNA level in the HCT116, DLD 1, and SW480 cell lines. ND: Not detected.

In this study, we examined whether CRH-related peptides acted via autocrine/paracrine mechanisms in colorectal cancer cell lines to influence DNA synthesis. Moreover, we reviewed whether CRH-related peptides played a role in the response to cellular stress caused by anticancer drugs and affected the effects of anticancer drugs (DNA synthesis disorder).

Materials and Methods

Three human colorectal cancer cell lines, HCT116, DLD-1, and SW480 (American Type Culture Collection, Rockville, MD, USA) were used.

UCN, UCN2, UCN3, CRHR1, and CRHR2 expression at the mRNA level in colorectal cancer cell lines was examined. After extracting total RNA from untreated cells using TRIZOL® Reagent (Invitrogen, Carlsbad, CA), RNAs were treated with RNase inhibitor and RNase-free recombinant DNase I (Takara Bio, Ohtsu, Japan). Then cDNA was prepared using TAKARA PrimeScript™RT Master Mix (Takara Bio). mRNA expression was examined using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) by the LightCycler® 96 System (Roche Diagnostics, Mannheim, Germany) at 95°C for 30 s followed by 40 cycles at 95°C for 5 s and then at 60°C for 30 s (CYBR Premix Ex TaqII) for each of the triplet samples. The quantification cycle value (Cq) of the target genes and internal reference gene glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were recorded.

The products were also analyzed by 10% polyacrylamide gel and visualized by ethidium bromide.

Forward/reverse primers used for genes: UCN: 5’-GTCCATTGACCTCACCTTTCA-3’/5’-GTCGAATATGATGCGGTTCTG-3’; UCN2: 5’-CTGACCTCACGATGACCAGG-3’/ 5’-AGCTGGAAGGTTGGGATAGGG-3’; UCN3: 5’-AGGCACCCGGTACAGATACG-3’/5’-GAGGGACAGGGTGAACTTGG-3’; CRHR1: 5’-GAACCCTGGAGACAGAAGTCA-3’/5’-AGTGCCA CAGTGCCAGTAAG-3’; CRHR2: 5’-CCTCTCTTGGGAGACC CCTT-3’/5’-CACGATGCAACTGGTTGACTA-3’; GAPDH: 5’-GAGCACAAGAGGAAGAGAGAGAC-3’/5’+TCTAC ATGGCAACTGTGAGGAG-3’.

Using fluorouracil (5-FU), the most widely used chemotherapy agent for colorectal cancer, we examined the changes in CRH-related peptide expression levels at the mRNA level in response to 5-FU-induced cellular stress for cell line HCT116. HCT116 cells were seeded (2×106 cells/25 cm2 flask) and cultured for 24 h. Then 5-FU was added at 2.8 μM, the half-inhibitory concentration (IC50) as determined by the methylene blue assay. The expression of UCN, UCN2, CRHR1, and CRHR2 at the mRNA level was examined before 5-FU (Sigma-Aldrich, Saint Louis, MO, USA) administration and 15 min, 30 min, and 1, 2, 4, 6, 12, 24, and 48 h after administration. We determined ΔCq (Cqtarget gene−CqGAPDH) and plotted the relative values after setting the expression level (before 5-FU addition) to 1(ΔΔCq method). Values are the means of experiments conducted in triplicate.

Colorectal cancer cells (HCT116, DLD-1, SW480) were seeded in 96-well flat bottom plates at 1×104 cells/well and cultured for 24 h. CRHR1 antagonist antalarmin and CRHR2 antagonist astressin 2B were added at 1 μM and cells were further cultured for 24 h. Controls without antagonists for each cell lines were also prepared. Since dimethyl sulfoxide was contained in the stock solution of antalarmin, dimethyl sulfoxide was added at the same concentration to the controls and astressin 2B-added samples. Then anticancer agents 5-FU (Sigma-Aldrich) or SN-38(Toronto Research Chemicals, Toronto, Canada) at the IC50 was added (5FU: 2.8, 9.9, 48.9 μM and SN-38: 23, 397, 141 nM for HCT116, DLD-1 and SW480, respectively), and 3H-labeled deoxyribonucleoside was added at 18.5 μCi/well for incubation 1 h after administration of anticancer agent. Cells were collected onto a Unifilter 96 GF/B® using Cell Harvester® after 8 h incubation, and MicroScint 20® was added (all PerkinElmer, Waltham, MA, USA). Then the amount of 3H-labeled deoxyribonucleoside taken up was calculated using a Hidex Sense Microplate Reader® (Hidex, Lemminkaisenkatu, Finland). Experiments were conducted in triplicate. Statistical analysis was performed by two sample t-test.

Figure 2.
Figure 2.

Expression of urocortin (UCN), UCN2, UCN3 corticotropin-releasing hormone-related peptides receptors CRHR1 and CRHR2 at the mRNA level in the HCT116 cell line before and after adding 5-fluororouracil (5-FU).

Results

UCN, UCN2, CRHR1, and CRHR2 (PCR product: 100 bp) expression at the mRNA level was recognized in all three cell lines (HCT116, DLD-1, and SW480). UCN3 was detected only in DLD-1. The Cq values are indicated in Figure 1.

In the HCT116 colorectal cancer cell line, no significant change in UCN, UCN2, CRHR1, and CRHR2 expression levels at the mRNA level was observed before/after 5-FU addition, as shown in Figure 2.

The results of the 3H-deoxycytidine uptake assay, including treatment with 5-FU, are shown in Figure 3. No significant difference was observed in DNA synthetic ability (3H-deoxycytidine uptake) with and without CRHR1 antagonist antalarmin and CRHR2 antagonist astressin 2B under 5-FU treatment.

The results of 3H-thymidine uptake assay, including treatment with SN-38, are shown in Figure 4; no significant difference was observed in the DNA synthesis ability with and without antalarmin and astressin 2B under SN-38 treatment.

Discussion

CRH-related peptide expression in various malignant tumors has been reported. UCN, UCN2, CRHR1, and CRHR2 expression at the mRNA level was observed in the HCT116, DLD-1, and SW480 cell lines in this study. It has been reported that CRH-related peptides are involved in various stress responses under physiological conditions (28, 36, 37). Therefore, we examined whether CRH-related peptide expression levels in cancer cell line (HCT116) changed in response to cellular stress caused by the addition of an anticancer drug. No change in the amounts of UCN, UCN2, CRHR1, and CRHR2 mRNA with 5-FU treatment was observed.

Figure 3.
Figure 3.

The results of the 3H-deoxycytidine uptake assay in cells with and without 5-fluororouracil (5-FU) treatment. Cont: Control; Ant: antalarmin, corticotropin-releasing hormone-related peptide receptor 1 antagonist; Ast2B: astressin 2B, corticotropin-releasing hormone-related peptide receptor 2 antagonist.

Figure 4.
Figure 4.

The results of 3H-thymidine uptake assay in cells with and without SN-38 treatment. Cont: Control; Ant: antalarmin, corticotropin-releasing hormone-related peptide receptor 1 antagonist; Ast2B: astressin 2B, corticotropin-releasing hormone-related peptide receptor 2 antagonist.

There are many reports on the potency of CRH-related peptides in cancer cell proliferation (18, 38, 39). Previous reports indicated that UCN suppressed cellular proliferation through CRHR2 in colorectal cancer (18), UCN and UCN2 promoted cellular proliferation through CRHR2 in stomach cancer (24), and UCN inhibited cellular proliferation in hepatocellular cancer (6). The effects of CRH-related peptides on the proliferation potency of cancer cells remain controversial. In this study, we examined whether CRH-related peptides act via autocrine/paracrine mechanisms and affect cell proliferation and evaluated the DNA synthesis ability of the cells based on their uptake of 3H-labeled deoxyribonucleoside. No significant difference was observed in the 3H-labeled deoxyribonucleoside uptake in each cell line with or without the addition of the CRHR1/CRHR2 antagonists, and hence, no difference in the DNA synthesis ability was observed. Hence, it is doubtful that CRH-related peptides affect the DNA synthesis ability of cells via autocrine/paracrine mechanisms.

Furthermore, we examined whether CRH-related peptides are involved in the resistance to cellular stress caused by anticancer drugs using 5-FU and SN-38. SN-38 is the active form of irinotecan. No significant differences in the 3H-labeled deoxyribonucleoside uptake with and without the addition of the CRHR1/CRHR2 antagonists were observed, and hence, no difference in the inhibitory effects of anticancer drugs on DNA synthesis was observed. Therefore, this result suggests that it is doubtful that CRH-related peptides affect the inhibitory effects of anticancer drugs on DNA synthesis via autocrine/paracrine mechanisms.

This study has several limitations based on the relationship between CRH-related peptides and DNA synthesis inhibition by anticancer drugs. Firstly, we examined the action of CRH-related peptides only via autocrine/paracrine mechanisms in this study. There is a possibility that CRH-related peptides control gene expression via non-autocrine/paracrine mechanism, such as peptide translocation into the nucleus to control gene expression related to cell proliferation (10). In the future, studies using cells overexpressing CRH-related peptides or cells in which UCN expression has been knocked down by small interfering RNA are required. Secondly, since the CRHR1/CRHR2 expression levels in the cell lines used in this study were low, it is possible that the effects of the peptides via autocrine/paracrine mechanisms were not recognized. Additional studies using cells with high CRHR1/CRHR2 expression obtained by gene transfer are required.

Conclusion

The expression levels of CRH-related peptides UCN and UCN2, and their receptors, CRHR1 and CRHR2, in colon cancer cell lines did not change in response to cellular stress caused by anticancer drugs 5-FU and SN-38. CRH-related peptides showed no effect on DNA synthesis in response to cellular stress caused by anticancer drugs.

Acknowledgements

The Authors thank Dr. Saburo Saito, Minori Kamada, and Mayumi Nomura for expert technical support. They also appreciate the contribution of the faculty of the Radioisotope Research Facilities.

Footnotes

  • Authors' Contributions

    GK and YM designed the study. GK carried out all experiments and drafted the article. KI and YM supervised all experiments performed. GK prepared the final article. As the principal investigator, YM supervised the study. All Authors read and approved the final article.

  • Conflicts of Interest

    The Authors declare they have no conflicts of interest regarding this study.

  • Received June 2, 2020.
  • Revision received June 20, 2020.
  • Accepted June 24, 2020.

References

  1. ↵
    1. Bray F,
    2. Ferlay J,
    3. Soerjomataram I,
    4. Siegel RL,
    5. Torre LA,
    6. Jemal A
    : Global cancer statistics 2018: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6): 394-424, 2018. PMID: 30207593. DOI: 10.3322/caac.21492
    OpenUrlCrossRefPubMed
  2. ↵
    1. Simmonds PC
    : Palliative chemotherapy for advanced colorectal cancer: Systematic review and meta-analysis. Colorectal Cancer Collaborative Group. BMJ 321(7260): 531-535, 2000. PMID: 10968812. DOI: 10.1136/bmj.321.7260.531
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Yamada Y,
    2. Takahari D,
    3. Matsumoto H,
    4. Baba H,
    5. Nakamura M,
    6. Yoshida K,
    7. Yoshida M,
    8. Iwamoto S,
    9. Shimada K,
    10. Komatsu Y,
    11. Sasaki Y,
    12. Satoh T,
    13. Takahashi K,
    14. Mishima H,
    15. Muro K,
    16. Watanabe M,
    17. Sakata Y,
    18. Morita S,
    19. Shimada Y,
    20. Sugihara K
    : Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus s-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): An open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol 14(13): 1278-1286, 2013. PMID: 24225157. DOI: 10.1016/s1470-2045(13)70490-x
    OpenUrlCrossRefPubMed
    1. Loupakis F,
    2. Cremolini C,
    3. Masi G,
    4. Lonardi S,
    5. Zagonel V,
    6. Salvatore L,
    7. Cortesi E,
    8. Tomasello G,
    9. Ronzoni M,
    10. Spadi R,
    11. Zaniboni A,
    12. Tonini G,
    13. Buonadonna A,
    14. Amoroso D,
    15. Chiara S,
    16. Carlomagno C,
    17. Boni C,
    18. Allegrini G,
    19. Boni L,
    20. Falcone A
    : Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 371(17): 1609-1618, 2014. PMID: 25337750. DOI: 10.1056/NEJMoa1403108
    OpenUrlCrossRefPubMed
  5. ↵
    1. Yamazaki K,
    2. Nagase M,
    3. Tamagawa H,
    4. Ueda S,
    5. Tamura T,
    6. Murata K,
    7. Eguchi Nakajima T,
    8. Baba E,
    9. Tsuda M,
    10. Moriwaki T,
    11. Esaki T,
    12. Tsuji Y,
    13. Muro K,
    14. Taira K,
    15. Denda T,
    16. Funai S,
    17. Shinozaki K,
    18. Yamashita H,
    19. Sugimoto N,
    20. Okuno T,
    21. Nishina T,
    22. Umeki M,
    23. Kurimoto T,
    24. Takayama T,
    25. Tsuji A,
    26. Yoshida M,
    27. Hosokawa A,
    28. Shibata Y,
    29. Suyama K,
    30. Okabe M,
    31. Suzuki K,
    32. Seki N,
    33. Kawakami K,
    34. Sato M,
    35. Fujikawa K,
    36. Hirashima T,
    37. Shimura T,
    38. Taku K,
    39. Otsuji T,
    40. Tamura F,
    41. Shinozaki E,
    42. Nakashima K,
    43. Hara H,
    44. Tsushima T,
    45. Ando M,
    46. Morita S,
    47. Boku N,
    48. Hyodo I
    : Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G). Ann Oncol 27(8): 1539-1546, 2016. PMID: 27177863. DOI: 10.1093/annonc/mdw206
    OpenUrlCrossRefPubMed
  6. ↵
    1. Wang J,
    2. Xu Y,
    3. Xu Y,
    4. Zhu H,
    5. Zhang R,
    6. Zhang G,
    7. Li S
    : Urocortin's inhibition of tumor growth and angiogenesis in hepatocellular carcinoma via corticotrophin-releasing factor receptor 2. Cancer Invest 26(4): 359-368, 2008. PMID: 18443956. DOI: 10.1080/07357900701788106
    OpenUrlCrossRefPubMed
    1. Minas V,
    2. Rolaki A,
    3. Kalantaridou SN,
    4. Sidiropoulos J,
    5. Mitrou S,
    6. Petsas G,
    7. Jeschke U,
    8. Paraskevaidis EA,
    9. Fountzilas G,
    10. Chrousos GP,
    11. Pavlidis N,
    12. Makrigiannakis A
    : Intratumoral CRH modulates immuno-escape of ovarian cancer cells through FASL regulation. Br J Cancer 97(5): 637-645, 2007. PMID: 17667919. DOI: 10.1038/sj.bjc.6603918
    OpenUrlCrossRefPubMed
    1. Graziani G,
    2. Tentori L,
    3. Portarena I,
    4. Barbarino M,
    5. Tringali G,
    6. Pozzoli G,
    7. Navarra P
    : Crh inhibits cell growth of human endometrial adenocarcinoma cells via CRH-receptor 1-mediated activation of cAMP-PKA pathway. Endocrinology 143(3): 807-813, 2002. PMID: 11861501. DOI: 10.1210/endo.143.3.8694
    OpenUrlCrossRefPubMed
    1. Tezval H,
    2. Jurk S,
    3. Atschekzei F,
    4. Serth J,
    5. Kuczyk MA,
    6. Merseburger AS
    : The involvement of altered corticotropin-releasing factor receptor 2 expression in prostate cancer due to alteration of anti-angiogenic signaling pathways. Prostate 69(4): 443-448, 2009. DOI: 10.1002/pros.20892
    OpenUrlCrossRefPubMed
  10. ↵
    1. Tezval H,
    2. Jurk S,
    3. Atschekzei F,
    4. Becker JU,
    5. Jahn O,
    6. Serth J,
    7. Kuczyk MA
    : Urocortin and corticotropin-releasing factor receptor 2 in human renal cell carcinoma: Disruption of an endogenous inhibitor of angiogenesis and proliferation. World J Urol 27(6): 825-830, 2009. PMID: 19058138. DOI: 10.1007/s00345-009-0417-x
    OpenUrlCrossRefPubMed
    1. Akiyoshi K,
    2. Kamada M,
    3. Fujioka K,
    4. Ikeda K,
    5. Tojo K,
    6. Manome Y
    : Expression of mrnas of urocortin in the STKM-1 gastric cancer cell line. Anticancer Res 33(12): 5289-5294, 2013. PMID: 24324061.
    OpenUrlAbstract/FREE Full Text
    1. Graziani G,
    2. Tentori L,
    3. Muzi A,
    4. Vergati M,
    5. Tringali G,
    6. Pozzoli G,
    7. Navarra P
    : Evidence that corticotropin-releasing hormone inhibits cell growth of human breast cancer cells via the activation of CRH-R1 receptor subtype. Mol Cell Endocrinol 264(1-2): 44-49, 2007. PMID: 17097220. DOI: 10.1016/j.mce.2006.10.006
    OpenUrlCrossRefPubMed
    1. Jin L,
    2. Chen C,
    3. Guo R,
    4. Wan R,
    5. Li S
    : Role of corticotropin-releasing hormone family peptides in androgen receptor and vitamin D receptor expression and translocation in human breast cancer MCF-7 cells. Eur J Pharmacol 684(1-3): 27-35, 2012. PMID: 22494987. DOI: 10.1016/j.ejphar.2012.03.034
    OpenUrlCrossRefPubMed
    1. Kamada M,
    2. Ikeda K,
    3. Fujioka K,
    4. Akiyama N,
    5. Akiyoshi K,
    6. Inoue Y,
    7. Hanada S,
    8. Yamamoto K,
    9. Tojo K,
    10. Manome Y
    : Expression of mRNAs of urocortin and corticotropin-releasing factor receptors in malignant glioma cell lines. Anticancer Res 32(12): 5299-5307, 2012. PMID: 23225430.
    OpenUrlAbstract/FREE Full Text
    1. Miceli F,
    2. Ranelletti FO,
    3. Martinelli E,
    4. Petrillo M,
    5. Scambia G,
    6. Navarra P,
    7. Ferrandina G
    : Expression and subcellular localization of CRH and its receptors in human endometrial cancer. Mol Cell Endocrinol 305(1-2): 6-11, 2009. PMID: 19433256. DOI: 10.1016/j.mce.2009.02.013
    OpenUrlCrossRefPubMed
    1. Reubi JC,
    2. Waser B,
    3. Vale W,
    4. Rivier J
    : Expression of CRF1 and CRF2 receptors in human cancers. J Clin Endocrinol Metab 88(7): 3312-3320, 2003. PMID: 12843181. DOI: 10.1210/jc.2002-021853
    OpenUrlCrossRefPubMed
  17. ↵
    1. Ikeda K,
    2. Fujioka K,
    3. Tachibana T,
    4. Kim SU,
    5. Tojo K,
    6. Manome Y
    : Secretion of urocortin I by human glioblastoma cell lines, possibly via the constitutive pathway. Peptides 63: 63-70, 2015. PMID: 25239507. DOI: 10.1016/j.peptides.2014.09.007
    OpenUrl
  18. ↵
    1. Rodriguez JA,
    2. Huerta-Yepez S,
    3. Law IK,
    4. Baay-Guzman GJ,
    5. Tirado-Rodriguez B,
    6. Hoffman JM,
    7. Iliopoulos D,
    8. Hommes DW,
    9. Verspaget HW,
    10. Chang L,
    11. Pothoulakis C,
    12. Baritaki S
    : Diminished expression of CRHR2 in human colon cancer promotes tumor growth and EMT via persistent IL-6/STAT3 signaling. Cell Mol Gastroenterol Hepatol 1(6): 610-630, 2015. PMID: 26495412. DOI: 10.1016/j.jcmgh.2015.08.001
    OpenUrl
  19. ↵
    1. Ducarouge B,
    2. Pelissier-Rota M,
    3. Laine M,
    4. Cristina N,
    5. Vachez Y,
    6. Scoazec JY,
    7. Bonaz B,
    8. Jacquier-Sarlin M
    : CRF2 signaling is a novel regulator of cellular adhesion and migration in colorectal cancer cells. PLoS One 8(11): e79335, 2013. PMID: 24260200. DOI: 10.1371/journal.pone.0079335
    OpenUrl
    1. Pelissier-Rota M,
    2. Chartier NT,
    3. Bonaz B,
    4. Jacquier-Sarlin MR
    : A crosstalk between muscarinic and CRF2 receptors regulates cellular adhesion properties of human colon cancer cells. Biochim Biophys Acta 1864(7): 1246-1259, 2017. PMID: 28432022. DOI: 10.1016/j.bbamcr.2017.04.008
    OpenUrl
  21. ↵
    1. Liu Y,
    2. Fang X,
    3. Yuan J,
    4. Sun Z,
    5. Li C,
    6. Li R,
    7. Li L,
    8. Zhu C,
    9. Wan R,
    10. Guo R,
    11. Jin L,
    12. Li S
    : The role of corticotropin-releasing hormone receptor 1 in the development of colitis-associated cancer in mouse model. Endocr Relat Cancer 21(4): 639-651, 2014. PMID: 25015995. DOI: 10.1530/erc-14-0239
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Deussing JM,
    2. Chen A
    : The corticotropin-releasing factor family: Physiology of the stress response. Physiol Rev 98(4): 2225-2286, 2018. PMID: 30109816. DOI: 10.1152/physrev.00042.2017
    OpenUrl
  23. ↵
    1. Bale TL,
    2. Vale WW
    : CRF and CRF receptors: Role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol 44: 525-557, 2004. PMID: 14744257. DOI: 10.1146/annurev.pharmtox.44.101802.121410
    OpenUrlCrossRefPubMed
  24. ↵
    1. Chatzaki E,
    2. Lambropoulou M,
    3. Constantinidis TC,
    4. Papadopoulos N,
    5. Tache Y,
    6. Minopoulos G,
    7. Grigoriadis DE
    : Corticotropin-releasing factor (CRF) receptor type 2 in the human stomach: Protective biological role by inhibition of apoptosis. J Cell Physiol 209(3): 905-911, 2006. PMID: 16972272. DOI: 10.1002/jcp.20792
    OpenUrlCrossRefPubMed
  25. ↵
    1. Dedic N,
    2. Chen A,
    3. Deussing JM
    : The CRF family of neuropeptides and their receptors - mediators of the central stress response. Curr Mol Pharmacol 11(1): 4-31, 2018. PMID: 28260504. DOI: 10.2174/1874467210666170302104053
    OpenUrl
  26. ↵
    1. Herman JP,
    2. McKlveen JM,
    3. Ghosal S,
    4. Kopp B,
    5. Wulsin A,
    6. Makinson R,
    7. Scheimann J,
    8. Myers B
    : Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr Physiol 6(2): 603-621, 2016. PMID: 27065163. DOI: 10.1002/cphy.c150015
    OpenUrl
  27. ↵
    1. Davidson SM,
    2. Rybka AE,
    3. Townsend PA
    : The powerful cardioprotective effects of urocortin and the corticotropin releasing hormone (CRH) family. Biochem Pharmacol 77(2): 141-150, 2009. PMID: 18817752. DOI: 10.1016/j.bcp.2008.08.033
    OpenUrlCrossRefPubMed
  28. ↵
    1. Taché Y,
    2. Perdue MH
    : Role of peripheral CRF signalling pathways in stress-related alterations of gut motility and mucosal function. Neurogastroenterol Motil 16 Suppl 1: 137-142, 2004. PMID: 15066020. DOI: 10.1111/j.1743-3150.2004.00490.x
    OpenUrlCrossRefPubMed
    1. Martinez V,
    2. Taché Y
    : CRF1 receptors as a therapeutic target for irritable bowel syndrome. Curr Pharm Des 12(31): 4071-4088, 2006. PMID: 17100612. DOI: 10.2174/138161206778743637
    OpenUrlCrossRefPubMed
  30. ↵
    1. Gourcerol G,
    2. Wu SV,
    3. Yuan PQ,
    4. Pham H,
    5. Miampamba M,
    6. Larauche M,
    7. Sanders P,
    8. Amano T,
    9. Mulak A,
    10. Im E,
    11. Pothoulakis C,
    12. Rivier J,
    13. Taché Y,
    14. Million M
    : Activation of corticotropin-releasing factor receptor 2 mediates the colonic motor coping response to acute stress in rodents. Gastroenterology 140(5): 1586-1596.e1586, 2011. PMID: 21277852. DOI: 10.1053/j.gastro.2011.01.039
    OpenUrlCrossRefPubMed
  31. ↵
    1. Baigent SM
    : Peripheral corticotropin-releasing hormone and urocortin in the control of the immune response. Peptides 22(5): 809-820, 2001. PMID: 11337095. DOI: 10.1016/s0196-9781(01)00395-3
    OpenUrlCrossRefPubMed
  32. ↵
    1. Owens GL,
    2. Lawrence KM,
    3. Jackson TR,
    4. Crosbie EJ,
    5. Sayan BS,
    6. Kitchener HC,
    7. Townsend PA
    : Urocortin suppresses endometrial cancer cell migration via CRFR2 and its system components are differentially modulated by estrogen. Cancer Med 6(2): 408-415, 2017. PMID: 28109061. DOI: 10.1002/cam4.967
    OpenUrl
    1. Pothoulakis C,
    2. Torre-Rojas M,
    3. Duran-Padilla MA,
    4. Gevorkian J,
    5. Zoras O,
    6. Chrysos E,
    7. Chalkiadakis G,
    8. Baritaki S
    : CRHR2/UCN2 signaling is a novel regulator of miR-7/YY1/FAS circuitry contributing to reversal of colorectal cancer cell resistance to FAS-mediated apoptosis. Int J Cancer 142(2): 334-346, 2018. PMID: 28929494. DOI: 10.1002/ijc.31064
    OpenUrl
    1. Zhu C,
    2. Sun Z,
    3. Li C,
    4. Guo R,
    5. Li L,
    6. Jin L,
    7. Wan R,
    8. Li S
    : Urocortin affects migration of hepatic cancer cell lines via differential regulation of cpla2 and ipla2. Cell Signal 26(5): 1125-1134, 2014. PMID: 24518041. DOI: 10.1016/j.cellsig.2014.02.002
    OpenUrlCrossRefPubMed
  35. ↵
    1. Pozzoli G,
    2. De Simone ML,
    3. Cantalupo E,
    4. Cenciarelli C,
    5. Lisi L,
    6. Boninsegna A,
    7. Dello Russo C,
    8. Sgambato A,
    9. Navarra P
    : The activation of type 1 corticotropin releasing factor receptor (CRF-R1) inhibits proliferation and promotes differentiation of neuroblastoma cells in vitro via p27 (KIP1) protein up-regulation and c-MYC mRNA down-regulation. Mol Cell Endocrinol 412: 205-215, 2015. PMID: 25960164. DOI: 10.1016/j.mce.2015.05.004
    OpenUrl
  36. ↵
    1. Larauche M,
    2. Kiank C,
    3. Tache Y
    : Corticotropin releasing factor signaling in colon and ileum: Regulation by stress and pathophysiological implications. J Physiol Pharmacol 60 Suppl 7:33-46, 2009. PMID: 20388944.
    OpenUrlPubMed
  37. ↵
    1. Ikeda K,
    2. Tojo K,
    3. Inada Y,
    4. Takada Y,
    5. Sakamoto M,
    6. Lam M,
    7. Claycomb WC,
    8. Tajima N
    : Regulation of urocortin I and its related peptide urocortin II by inflammatory and oxidative stresses in HL-1 cardiomyocytes. J Mol Endocrinol 42(6): 479-489, 2009. PMID: 19318426. DOI: 10.1677/jme-08-0151
    OpenUrlAbstract/FREE Full Text
  38. ↵
    1. Hao Z,
    2. Huang Y,
    3. Cleman J,
    4. Jovin IS,
    5. Vale WW,
    6. Bale TL,
    7. Giordano FJ
    : Urocortin2 inhibits tumor growth via effects on vascularization and cell proliferation. Proc Natl Acad Sci USA 105(10): 3939-3944, 2008. PMID: 18308934. DOI: 10.1073/pnas.0712366105
    OpenUrlAbstract/FREE Full Text
  39. ↵
    1. Carlson KW,
    2. Nawy SS,
    3. Wei ET,
    4. Sadée W,
    5. Filov VA,
    6. Rezsova VV,
    7. Slominski A,
    8. Quillan JM
    : Inhibition of mouse melanoma cell proliferation by corticotropin-releasing hormone and its analogs. Anticancer Res 21(2a): 1173-1179, 2001. PMID: 11396159.
    OpenUrlPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Involvement of Corticotropin-releasing Hormone-related Peptides in Cellular Stress Caused by Anticancer Drugs in Colorectal Cancer
GO KUWATA, KEIICHI IKEDA, YOSHINOBU MANOME
Anticancer Research Aug 2020, 40 (8) 4505-4511; DOI: 10.21873/anticanres.14455
Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords