Calcium, calcium-sensing receptor and colon cancer

Abstract 

There is much evidence that dietary Ca²⁺ loading reduces colon cell proliferation and carcinogenesis in humans and rodents, but during carcinogenesis it becomes ineffective or even tumor-promoting. We are beginning to see how Ca²⁺ balances the continuous massive cell production in colon crypts by driving the terminal differentiation and eventually the apoptosis of the cells mainly on the mucosal surface, and how this Ca²⁺ control is lost during colon carcinogenesis. The rapid proliferation of the transit-amplifying (TA) progeny of the colon stem cells is driven by the so-called “Wnt” signaling mechanism, which involves the stimulation of proliferogenic genes such as those for c-Myc and cyclin D1 and the silencing of the gene for the cell cycle-stopping p21^Cip1/WAF1 protein by nuclear β-catenin•Tcf-4 complexes. TA cells avoid mitotic damage and premature apoptosis by expressing the protein survivin. It appears that TA cell cycling stops and terminal differentiation starts when the cells reach a higher level in the crypt where there is enough lumenal Ca²⁺ to stimulate the expression and activation of CaSRs (Ca²⁺-sensing receptors), the signals from which stimulate the expression of E-cadherin. Along with this, the APC (adenomatous polyposis coli) protein appears and some of it enters the nucleus. There it makes the TA cells susceptible to the eventual apoptotic balancing by stopping survivin expression and the β-catenin•Tcf-4 complex from driving further cell cycling by releasing β-catenin from the nucleus, and delivering it to cytoplasmic APC•axin•GSK-3β complexes for ultimate proteasomal destruction. Cytoplasmic β-catenin is then prevented from returning to the nucleus by either being intercepted and destroyed by APC•axin•GSK-3β complexes or locked by the emerging E-cadherin into membrane adherens junctions which tie the cell into the sheet of proliferatively shut-down cells with APC-dependent cytoskeletons moving to the mouth of the crypt and onto the flat mucosal surface. A common first step in sporadic colon carcinogenesis is the loss of functional APC which disorients upwardly directed migration and causes the retention of nuclear β-catenin and proliferogenic β-catenin•Tcf-4 complexes as well as genomic instability. Eventually the balance between cell proliferation and terminal differentiation and death is radically tipped in favour of proliferation by the appearance of apoptosis-resistant, survivin-expressing clones of Ca²⁺-insensitve cells which are locked into the proliferative, mutation-prone mode because of CaSR-disabling gene mutations which prevent the stimulation of E-cadherin expression and terminal differentiation.

Abbreviations: APC, adenomatous polyposis coli, AOM, azoxymethane, β-TrCP-E3 ligase, β-transducin repeat-containing protein-E3 ubiquitin ligase, CaMK II and IV, Ca²⁺•calmodulin-activated protein kinases II and IV, CaSR, Ca²⁺-sensing receptor, cdk, cyclin-dependent protein kinases, CKI, casein kinase I, CpG island, genomic islands with 300–30,000 CG dinucleotides, Fzp, Wnt protein’s frizzled receptor, GSK-3β, glycogen synthase kinase-3β, LRP, low-density lipoprotein receptor-related protein, p21^Cip1/WAF1p27^Kip1, 21kDa protein inhibitors of cyclin-dependent protein kinases, TA cell, transit-amplifying cell, Tcf-4, T-cell factor-4, TP53, 53kDa tumor-suppressor protein, TRPV6, transit receptor potential cation channel V subfamily 6, Wnt, wingless-int mammalian signal proteins

Keywords: APC, Apoptosis, β-catenin, Ca²⁺, CaSR