title: Malignant transformation of normal enterocytes following downregulation of Bak expression.
abstract: Bak is a pro-apoptotic gene, which plays an important role in the multi-step process of gastrointestinal tumorigenesis. We hypothesized that downregulation of Bak expression in normal enterocytes will result in a transformed phenotype. The nontumorigenic intestinal epithelial cell line (IEC18) was transfected with the vector pMV12-AS-bak (encoding anti-sense bak). Three clones, with Bak protein levels similar to those seen in colon cancer cell lines and significantly lower than those found in the parental cells, were further evaluated. The three clones proliferated faster, demonstrated anchorage-independent growth in soft agar and a higher saturation density and plating efficiency. Furthermore, when injected into nude mice, these cells generated tumors after approximately 2-3 weeks. The cells were more resistant to the induction of apoptosis by sulindac sulfide and sulindac sulfone but more sensitive to COX 2 inhibitors (celecoxib and nimesulide). The levels of p16, cyclin D1 and COX 2 were higher in the three transformed clones. In summary,downregulation of Bak expression in normal enterocytes contributes to abnormal growth and tumorigenesis. COX 2 inhibitors may serve as important agents in the prevention and treatment of CRC as they only inhibit the growth of malignant cells.
authors: Integrated Cancer Prevention Center, Tel Aviv Medical Center, Tel Aviv, Israel.
authors: Eliezer
authors: E
authors: Liberman
authors: Inna
authors: I
authors: Naumov
authors: Diana
authors: D
authors: Kazanov
authors: Hadas
authors: H
authors: Dvory-Sobol
authors: Eyal
authors: E
authors: Sagiv
authors: Shlomo
authors: S
authors: Birkenfeld
authors: Varda
authors: V
authors: Deutsch
authors: Luba
authors: L
authors: Trakhtenbrot
authors: Menachem
authors: M
authors: Moshkowitz
authors: Nadir
authors: N
authors: Arber
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000556:secondary; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology / Q000473:pathology; D015232:Dinoprostone / Q000378:metabolism; D015536:Down-Regulation; D020895:Enterocytes / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D014162:Transfection; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D050998:bcl-2 Homologous Antagonist-Killer Protein; D015232:Dinoprostone