Involvement of Src and the actin cytoskeleton in the antitumorigenic action of adenosine dialdehyde.
Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, AdOx disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src kinase activity.
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Ji Hye
JH
Kim
Yong Gyu
YG
Lee
Seungwan
S
Yoo
Jueun
J
Oh
Deok
D
Jeong
Woo Keun
WK
Song
Byong Chul
BC
Yoo
Man Hee
MH
Rhee
Jongsun
J
Park
Sang-Hoon
SH
Cha
Sungyoul
S
Hong
Jae Youl
JY
Cho
D008841:Actin Cytoskeleton / Q000502:physiology*; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D043383:Adenosylhomocysteinase / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D008745:Methylation; D010766:Phosphorylation; D051381:Rats; D012435:S-Adenosylhomocysteine / Q000494:pharmacology; D019061:src-Family Kinases / Q000502:physiology*
D000970:Antineoplastic Agents; C027579:periodate-oxidized adenosine; D012435:S-Adenosylhomocysteine; D019061:src-Family Kinases; D043383:Adenosylhomocysteinase; D000241:Adenosine