Increased extracellular pressure stimulates tumor proliferation by a mechanosensitive calcium channel and PKC-β

Mol Oncol. 2015 Feb;9(2):513-26. doi: 10.1016/j.molonc.2014.10.008. Epub 2014 Oct 23.


Large tumors exhibit high interstitial pressure heightened by growth against the constraining stroma. Such pressures could stimulate tumor proliferation via a mechanosensitive ion channel. We studied the effects of 0-80 mmHg increased extracellular pressure for 24 h on proliferation of SW620, Caco-2, and CT-26 colon; MCF-7 breast; and MLL and PC3 prostate cancer cells, and delineated its mechanism in SW620 cells with specific inhibitors and siRNA. Finally, we compared NF-kB, phospho-IkB and cyclin D1 immunoreactivity in the high pressure centers and low pressure peripheries of human tumors. Pressure-stimulated proliferation in all cells. Pressure-driven SW620 proliferation required calcium influx via the T-type Ca(2+) channel Cav3.3, which stimulated PKC-β to invoke the IKK-IkB-NF-kB pathway to increase proliferation and S-phase fraction. The mitotic index and immunoreactivity of NF-kB, phospho-IkB, and cyclin D1 in the center of 28 large human colon, lung, and head and neck tumors exceeded that in tumor peripheries. Extracellular pressure increases [Ca(2+)]i via Cav3.3, driving a PKC-β- IKK- IkB-NF-kB pathway that stimulates cancer cell proliferation. Rapid proliferation in large stiff tumors may increase intratumoral pressure, activating this pathway to stimulate further proliferation in a feedback cycle that potentiates tumor growth. Targeting this pathway may inhibit proliferation in large unresectable tumors.

Keywords: Calcium channels; Cav3.3; NF-kB; PKC; Pressure; Proliferation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Caco-2 Cells
  • Calcium Channels, T-Type / genetics
  • Calcium Channels, T-Type / metabolism*
  • Cell Proliferation*
  • Humans
  • Mice
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Pressure*
  • Protein Kinase C beta / genetics
  • Protein Kinase C beta / metabolism*
  • Rats
  • Signal Transduction*


  • CACNA1I protein, human
  • Cacna1i protein, mouse
  • Cacna1i protein, rat
  • Calcium Channels, T-Type
  • Neoplasm Proteins
  • Protein Kinase C beta