Skip to main content
NCBI home page
Cellular & Molecular Biology Letters logoLink to Cellular & Molecular Biology Letters
. 2011 Sep 12;16(4):625. doi: 10.2478/s11658-011-0027-7

DU-145 prostate carcinoma cells that selectively transmigrate narrow obstacles express elevated levels of Cx43

Katarzyna Szpak 1, Ewa Wybieralska 1, Ewa Niedziałkowska 1, Monika Rak 1, Iga Bechyne 1, Marta Michalik 1, Zbigniew Madeja 1, Jarosław Czyż 1,✉
PMCID: PMC6275569  PMID: 21910090

Abstract

The formation of aqueous intercellular channels mediating gap junctional intercellular coupling (GJIC) is a canonical function of connexins (Cx). In contrast, mechanisms of GJIC-independent involvement of connexins in cancer formation and metastasis remain a matter of debate. Because of the role of Cx43 in the determination of carcinoma cell invasive potential, we addressed the problem of the possible Cx43 involvement in early prostate cancer invasion. For this purpose, we analysed Cx43-positive DU-145 cell subsets established from the progenies of the cells most readily transmigrating microporous membranes. These progenies displayed motile activity similar to the control DU-145 cells but were characterized by elevated Cx43 expression levels and GJIC intensity. Thus, apparent links exist between Cx43 expression and transmigration potential of DU-145 cells. Moreover, Cx43 expression profiles in the analysed DU-145 subsets were not affected by intercellular contacts and chemical inhibition of GJIC during the transmigration. Our observations indicate that neither cell motility nor GJIC determines the transmigration efficiency of DU-145 cells. However, we postulate that selective transmigration of prostate cancer cells expressing elevated levels of Cx43 expression may be crucial for the “leading front” formation during cancer invasion.

Key words: Cancer invasion, Cell heterogeneity, Cell motility, Cx43, Gap junctions, Metastasis, Prostate cancer, Transmigration

Full Text

The Full Text of this article is available as a PDF (912.8 KB).

Abbreviations used

AGA

18-α-glycyrrhetinic acid

ARCD

average rate of cell displacement

ASCM

average speed of cell movement

Cr

coupling ratio

Cx43

connexin43

DMEM

Dulbecco modified Eagle’s medium

FBS

fetal bovine serum

GJIC

gap junctional intercellular coupling

Footnotes

Contributed equally

References

  • 1.Sohl G., Willecke K. Gap junctions and the connexin protein family. Cardiovasc. Res. 2004;62:228–232. doi: 10.1016/j.cardiores.2003.11.013. [DOI] [PubMed] [Google Scholar]
  • 2.Zhang Y.W., Kaneda M., Morita I. The gap junction-independent tumor-suppressing effect of connexin 43. J. Biol. Chem. 2003;278:44852–44856. doi: 10.1074/jbc.M305072200. [DOI] [PubMed] [Google Scholar]
  • 3.Omori Y., Li Q., Nishikawa Y., Yoshioka T., Yoshida M., Nishimura T., Enomoto K. Pathological significance of intracytoplasmic connexin proteins: implication in tumor progression. J. Membr. Biol. 2007;218:73–77. doi: 10.1007/s00232-007-9048-6. [DOI] [PubMed] [Google Scholar]
  • 4.Cronier L., Crespin S., Strale P.O., Defamie N., Mesnil M. Gap junctions and cancer: new functions for an old story. Antioxid. Redox. Signal. 2009;11:323–338. doi: 10.1089/ars.2008.2153. [DOI] [PubMed] [Google Scholar]
  • 5.Ionta M., Ferreira R.A., Pfister S.C., Machado-Santelli G.M. Exogenous Cx43 expression decrease cell proliferation rate in rat hepatocarcinoma cells independently of functional gap junction. Cancer Cell Int. 2009;9:22. doi: 10.1186/1475-2867-9-22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Elias L.A., Wang D.D., Kriegstein A.R. Gap junction adhesion is necessary for radial migration in the neocortex. Nature. 2007;448:901–907. doi: 10.1038/nature06063. [DOI] [PubMed] [Google Scholar]
  • 7.Wiencken-Barger A.E., Djukic B., Casper K.B., McCarthy K.D. A role for Connexin43 during neurodevelopment. Glia. 2007;55:675–686. doi: 10.1002/glia.20484. [DOI] [PubMed] [Google Scholar]
  • 8.Lin J.H., Yang J., Liu S., Takano T., Wang X., Gao Q., Willecke K., Nedergaard M. Connexin mediates gap junction-independent resistance to cellular injury. J. Neurosci. 2003;23:430–441. doi: 10.1523/JNEUROSCI.23-02-00430.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Xu X., Francis R., Wei C.J., Linask K.L., Lo C.W. Connexin 43-mediated modulation of polarized cell movement and the directional migration of cardiac neural crest cells. Development. 2006;133:3629–3639. doi: 10.1242/dev.02543. [DOI] [PubMed] [Google Scholar]
  • 10.Olk S., Zoidl G., Dermietzel R. Connexins, cell motility, and the cytoskeleton. Cell Motil. Cytoskeleton. 2009;66:1000–1016. doi: 10.1002/cm.20404. [DOI] [PubMed] [Google Scholar]
  • 11.Laird D.W. Life cycle of connexins in health and disease. Biochem. J. 2006;394:527–543. doi: 10.1042/BJ20051922. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Trosko J.E. Gap junctional intercellular communication as a biological “Rosetta stone” in understanding, in a systems biological manner, stem cell behavior, mechanisms of epigenetic toxicology, chemoprevention and chemotherapy. J. Membr. Biol. 2007;218:93–100. doi: 10.1007/s00232-007-9072-6. [DOI] [PubMed] [Google Scholar]
  • 13.Miekus K., Czernik M., Sroka J., Czyz J., Madeja Z. Contact stimulation of prostate cancer cell migration: the role of gap junctional coupling and migration stimulated by heterotypic cell-to-cell contacts in determination of the metastatic phenotype of Dunning rat prostate cancer cells. Biol. Cell. 2005;97:893–903. doi: 10.1042/BC20040129. [DOI] [PubMed] [Google Scholar]
  • 14.Bates D.C., Sin W.C., Aftab Q., Naus C.C. Connexin43 enhances glioma invasion by a mechanism involving the carboxy terminus. Glia. 2007;55:1554–1564. doi: 10.1002/glia.20569. [DOI] [PubMed] [Google Scholar]
  • 15.Czyz J. The stage-specific function of gap junctions during tumourigenesis. Cell Mol. Biol. Lett. 2008;13:92–102. doi: 10.2478/s11658-007-0039-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Zhang W., DeMattia J.A., Song H., Couldwell W.T. Communication between malignant glioma cells and vascular endothelial cells through gap junctions. J. Neurosurg. 2003;98:846–853. doi: 10.3171/jns.2003.98.4.0846. [DOI] [PubMed] [Google Scholar]
  • 17.Pollmann M.A., Shao Q., Laird D.W., Sandig M. Connexin 43 mediated gap junctional communication enhances breast tumor cell diapedesis in culture. Breast Cancer Res. 2005;7:R522–R534. doi: 10.1186/bcr1042. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Prochnow N., Dermietzel R. Connexons and cell adhesion: a romantic phase. Histochem. Cell Biol. 2008;130:71–77. doi: 10.1007/s00418-008-0434-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Boiko A.D., Razorenova O.V., van de R.M., Swetter S.M., Johnson D.L., Ly D.P., Butler P.D., Yang G.P., Joshua B., Kaplan M.J., Longaker M.T., Weissman I.L. Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature. 2010;466:133–137. doi: 10.1038/nature09161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Visvader J.E. Cells of origin in cancer. Nature. 2011;469:314–322. doi: 10.1038/nature09781. [DOI] [PubMed] [Google Scholar]
  • 21.Wysoczynski M., Miekus K., Jankowski K., Wanzeck J., Bertolone S., Janowska-Wieczorek A., Ratajczak J., Ratajczak M. Z. Leukemia inhibitory factor: a newly identified metastatic factor in rhabdomyosarcomas. Cancer Res. 2007;67:2131–2140. doi: 10.1158/0008-5472.CAN-06-1021. [DOI] [PubMed] [Google Scholar]
  • 22.Sroka J., Kaminski R., Michalik M., Madeja Z., Przestalski S., Korohoda W. The effect of triethyllead on the motile activity of walker 256 carcinosarcoma cells. Cell Mol. Biol. Lett. 2004;9:15–30. [PubMed] [Google Scholar]
  • 23.Sroka J., Antosik A., Czyz J., Nalvarte I., Olsson J.M., Spyrou G., Madeja Z. Overexpression of thioredoxin reductase 1 inhibits migration of HEK-293 cells. Biol. Cell. 2007;99:677–687. doi: 10.1042/BC20070024. [DOI] [PubMed] [Google Scholar]
  • 24.Czyz J., Guan K., Zeng Q., Wobus A.M. Loss of beta1 integrin function results in upregulation of connexin expression in embryonic stem cell-derived cardiomyocytes. Int. J. Dev. Biol. 2005;49:33–41. doi: 10.1387/ijdb.041835jc. [DOI] [PubMed] [Google Scholar]
  • 25.Daniel-Wojcik A., Misztal K., Bechyne I., Sroka J., Miekus K., Madeja Z., Czyz J. Cell motility affects the intensity of gap junctional coupling in prostate carcinoma and melanoma cell populations. Int. J. Oncol. 2008;33:309–315. [PubMed] [Google Scholar]
  • 26.Czyz J., Irmer U., Schulz G., Mindermann A., Hulser D.F. Gap-junctional coupling measured by flow cytometry. Exp. Cell Res. 2000;255:40–46. doi: 10.1006/excr.1999.4760. [DOI] [PubMed] [Google Scholar]
  • 27.Sottoriva A., Verhoeff J.J., Borovski T., McWeeney S.K., Naumov L., Medema J.P., Sloot P.M., Vermeulen L. Cancer stem cell tumor model reveals invasive morphology and increased phenotypical heterogeneity. Cancer Res. 2010;70:46–56. doi: 10.1158/0008-5472.CAN-09-3663. [DOI] [PubMed] [Google Scholar]
  • 28.Baran B., Bechyne I., Siedlar M., Szpak K., Mytar B., Sroka J., Laczna E., Madeja Z., Zembala M., Czyz J. Blood monocytes stimulate migration of human pancreatic carcinoma cells in vitro: the role of tumour necrosis factor — alpha. Eur. J. Cell Biol. 2009;88:743–752. doi: 10.1016/j.ejcb.2009.08.002. [DOI] [PubMed] [Google Scholar]
  • 29.Kumar S., Weaver V.M. Mechanics, malignancy, and metastasis: the force journey of a tumor cell. Cancer Metastasis Rev. 2009;28:113–127. doi: 10.1007/s10555-008-9173-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Friedl P., Wolf K. Plasticity of cell migration: a multiscale tuning model. J. Exp. Med. 2010;207:11–19. doi: 10.1084/JEM2071OIA4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Gupta G.P., Massague J. Cancer metastasis: building a framework. Cell. 2006;127:679–695. doi: 10.1016/j.cell.2006.11.001. [DOI] [PubMed] [Google Scholar]
  • 32.Langley R.R., Fidler I.J. Tumor cell-organ microenvironment interactions in the pathogenesis of cancer metastasis. Endocr. Rev. 2007;28:297–321. doi: 10.1210/er.2006-0027. [DOI] [PubMed] [Google Scholar]
  • 33.Watanabe N., Dickinson D.A., Krzywanski D.M., Iles K.E., Zhang H., Venglarik C.J., Forman H.J. A549 subclones demonstrate heterogeneity in toxicological sensitivity and antioxidant profile. Am. J. Physiol Lung Cell Mol. Physiol. 2002;283:L726–L736. doi: 10.1152/ajplung.00025.2002. [DOI] [PubMed] [Google Scholar]
  • 34.Blick T., Widodo E., Hugo H., Waltham M., Lenburg M.E., Neve R.M., Thompson E.W. Epithelial mesenchymal transition traits in human breast cancer cell lines. Clin. Exp. Metastasis. 2008;25:629–642. doi: 10.1007/s10585-008-9170-6. [DOI] [PubMed] [Google Scholar]
  • 35.Ito A., Katoh F., Kataoka T.R., Okada M., Tsubota N., Asada H., Yoshikawa K., Maeda S., Kitamura Y., Yamasaki H., Nojima H. A role for heterologous gap junctions between melanoma and endothelial cells in metastasis. J. Clin. Invest. 2000;105:1189–1197. doi: 10.1172/JCI8257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Huang S., Ingber D.E. Cell tension, matrix mechanics, and cancer development. Cancer Cell. 2005;8:175–176. doi: 10.1016/j.ccr.2005.08.009. [DOI] [PubMed] [Google Scholar]
  • 37.Suresh S. Biomechanics and biophysics of cancer cells. Acta Biomater. 2007;3:413–438. doi: 10.1016/j.actbio.2007.04.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Kanczuga-Koda L., Sulkowski S., Lenczewski A., Koda M., Wincewicz A., Baltaziak M., Sulkowska M. Increased expression of connexins 26 and 43 in lymph node metastases of breast cancer. J. Clin. Pathol. 2006;59:429–433. doi: 10.1136/jcp.2005.029272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Iwasaki H., Suda T. Cancer stem cells and their niche. Cancer Sci. 2009;100:1166–1172. doi: 10.1111/j.1349-7006.2009.01177.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Voog J., Jones D.L. Stem cells and the niche: a dynamic duo. Cell Stem Cell. 2010;6:103–115. doi: 10.1016/j.stem.2010.01.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Friedl P., Hegerfeldt Y., Tusch M. Collective cell migration in morphogenesis and cancer. Int. J. Dev. Biol. 2004;48:441–449. doi: 10.1387/ijdb.041821pf. [DOI] [PubMed] [Google Scholar]

Articles from Cellular & Molecular Biology Letters are provided here courtesy of BMC

RESOURCES