title: Increased extracellular pressure stimulates tumor proliferation by a mechanosensitive calcium channel and PKC-β.
abstract: 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.
authors.affiliation: Department of Surgery, Michigan State University College of Human Medicine, 1200 E Michigan Ave, Lansing Charter Township, MI 48912, USA. Electronic address: mdbasson@gmail.com.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Basson
authors.affiliation: Department of Surgery, Michigan State University College of Human Medicine, 1200 E Michigan Ave, Lansing Charter Township, MI 48912, USA.
authors.forename: Bixi
authors.initials: B
authors.lastname: Zeng
authors.affiliation: Department of Surgery, Michigan State University College of Human Medicine, 1200 E Michigan Ave, Lansing Charter Township, MI 48912, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Downey
authors.affiliation: Department of Surgery, Michigan State University College of Human Medicine, 1200 E Michigan Ave, Lansing Charter Township, MI 48912, USA.
authors.forename: Madhu P
authors.initials: MP
authors.lastname: Sirivelu
authors.affiliation: Department of Pharmacology, Michigan State University, 1355 Bogue Street, B440 Life Sciences Building, East Lansing, MI 48824, USA.
authors.forename: Jetze J
authors.initials: JJ
authors.lastname: Tepe
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011312:Pressure; D064546:Protein Kinase C beta / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction
chemical_list: C469757:CACNA1I protein, human; C534770:Cacna1i protein, mouse; C583277:Cacna1i protein, rat; D020747:Calcium Channels, T-Type; D009363:Neoplasm Proteins; D064546:Protein Kinase C beta
keywords: Calcium channels; Cav3.3; NF-kB; PKC; Pressure; Proliferation