The tumor promoter receptor protein kinase C: a novel target for chemoprevention and therapy of human colon cancer.
The high affinity receptor of phorbol-ester and related tumor promoters is the isozyme family protein kinase C (PKC). Activation of PKC by the phorbol esters is a pivotal event in phorbol ester-mediated tumor promotion. PKC activation is also implicated in tumor promotion of colonic epithelial cells by endogenous and dietary factors such as bile acids, free fatty acids, and diacylglycerols, suggesting that suppression of the inappropriate activation of colonic epithelial PKC by these factors could be an effective strategy of chemoprevention. Phorbol-ester tumor promoters induce pleiotropic resistance against anti-cancer drugs in cultured human colon cancer cells. By characterizing PKC isozyme expression in the cells and the induction of resistance by isozyme-selective PKC activators, we have obtained evidence that the induction of resistance is triggered by phorbol-ester activation of cPKC-alpha. We have also found that cPKC-alpha is expressed abundantly in surgical specimens of human colon cancer, indicating that cPKC-alpha-mediated drug resistance may contribute to the intrinsic drug resistance of clinical colon cancer. The intrinsic resistance of human colon cancer to multiple anticancer drugs precludes effective therapy of disseminated disease with available chemotherapeutic regimens. The development of reversal agents of intrinsic drug resistance that function by selective inhibition of cPKC-alpha might allow successful management of the disease with standard cytotoxic chemotherapeutic regimens.
O'Brian
C A
CA
Department of Cell Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Ward
N E
NE
Gravitt
K R
KR
Gupta
K P
KP
D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D004789:Enzyme Activation; D006801:Humans; D010704:Phorbols; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism; D011955:Receptors, Drug / Q000187:drug effects* / Q000378:metabolism
D016588:Anticarcinogenic Agents; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D010704:Phorbols; D011955:Receptors, Drug; C083141:phorbol ester binding protein; C027776:phorbol ester receptor; D011493:Protein Kinase C