Spermine synthase overexpression in vivo does not increase susceptibility to DMBA/TPA skin carcinogenesis or Min-Apc intestinal tumorigenesis

Abstract

Numerous studies have demonstrated a link between elevated polyamine biosynthesis and neoplastic growth, but the specific contribution of spermine synthase to epithelial tumor development has never been explored in vivo. Mice with widespread overexpression of spermine synthase (CAG-SpmS) exhibit decreased spermidine levels, increased spermine and a significant rise in tissue spermine:spermidine ratio. We characterized the response of CAG-SpmS mice to two-stage skin chemical carcinogenesis as well as spontaneous intestinal carcinogenesis induced by loss of the Apc tumor suppressor in Apc (Min) (/+) (Min) mice. CAG-SpmS mice maintained the canonical increases in ornithine decarboxylase (ODC) activity, polyamine content and epidermal thickness in response to tumor promoter treatment of the skin. The induction of S-adenosylmethionine decarboxylase (AdoMetDC) activity and its product decarboxylated AdoMet were impaired in CAG-SpmS mice, and the spermine:spermidine ratio was increased 3-fold in both untreated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated skin. The susceptibility to 7,12-dimethylbenz[a]anthracene (DMBA)/TPA skin carcinogenesis was not altered in CAG-SpmS mice, and SpmS overexpression did not modify the previously described tumor resistance of mice with targeted antizyme expression or the enhanced tumor response in mice with targeted spermidine/spermine-N ( 1) -acetyltransferase expression. CAG-SpmS/Min mice also exhibited elevated spermine:spermidine ratios in the small intestine and colon, yet their tumor multiplicity and size was similar to Min mice. Therefore, studies in two of the most widely used tumorigenesis models demonstrate that increased spermine synthase activity and the resulting elevation of the spermine:spermidine ratio does not alter susceptibility to tumor development initiated by c-Ha-Ras mutation or Apc loss.

Targeting autophagy with small molecules for cancer therapy

“…Very recent immunoprecipitation and immunohistochemistry studies in human chondrocytes and in vivo study conducted in mice reported that the cells treated with spermidine (100 nmol/L) showed autophagy activation and promoted chondrogenesis [98] . However, spermidne role in cancer is still controversial as some studies reported that spermidine do not induce tumorigenesis [99] , whereas some studies established that spermidine synthase inhibitors show little cell growth reduction in cancer cell lines [100] .…”

Elevated ornithine decarboxylase activity promotes skin tumorigenesis by stimulating the recruitment of bulge stem cells but not via toxic polyamine catabolic metabolites

“…Indeed, increased epidermal AdoMetDC expression suppresses skin tumor promotion in DMBA-initiated/TPA-promoted mice (Shi et al 2012). Moreover, increased epidermal spermine synthase activity has no effect on skin tumor development in transgenic mice subjected to a DMBA/TPA carcinogenesis protocol (Welsh et al 2012). Surprisingly, K6/SSAT transgenic mice with increased epidermal expression of SSAT are more sensitive to skin tumor development when subjected to a DMBA initiation/TPA promotion protocol (Coleman et al 2002).…”

Spermine synthase and MYC cooperate to maintain colorectal cancer cell survival by repressing Bim expression

“…Dysregulation of MYC is a consequence of mutations in APC, a central hub in early colorectal carcinogenesis 58 . In a mouse model of Min-Apc intestinal tumorigenesis, mice that overexpressed SMS display similar colon tumor multiplicity and size compared with multiple intestinal neoplasia as seen in the Min mice 59 . Together, these data suggest that SMS alone does not promote CRC tumorigenesis.…”