Abstract
The S-adenosylmethionine (AdoMet) salvage enzyme 5'-methylthioadenosine phosphorylase (MTAP) has been implicated as both a cancer target and a tumor suppressor. We tested these hypotheses in mouse xenografts of human lung cancers. AdoMet recycling from 5'-methylthioadenosine (MTA) was blocked by inhibition of MTAP with methylthio-DADMe-Immucillin-A (MTDIA), an orally available, nontoxic, picomolar transition state analogue. Blood, urine, and tumor levels of MTA increased in response to MTDIA treatment. MTDIA treatment inhibited A549 (human non-small cell lung carcinoma) and H358 (human bronchioloalveolar non-small cell lung carcinoma cells) xenograft tumor growth in immunodeficient Rag2(-/-)γC(-/-) and NCr-nu mice. Systemic MTA accumulation is implicated as the tumor-suppressive metabolite because MTDIA is effective for in vivo treatment of A549 MTAP(-/-) and H358 MTAP(+/+) tumors. Tumors from treated mice showed increased MTA and decreased polyamines but little alteration in AdoMet, methionine, or adenine levels. Gene expression profiles of A549 tumors from treated and untreated mice revealed only modest alterations with 62 up-regulated and 63 down-regulated mRNAs (≥ 3-fold). MTDIA antitumor activity in xenografts supports MTAP as a target for lung cancer therapy.
Highlights
Donor for biosynthetic methylation reactions, a precursor for polyamine synthesis, and the source of methyl groups for DNA methylation
Others have proposed that methylthioadenosine phosphorylase (MTAP) is a tumor suppressor gene [3], and experiments here explore the effects of MTAP inhibition in human lung cancer xenografts
We previously demonstrated that treatment of human FaDu head and neck tumors in mouse xenografts with MTDIA prevented tumor growth with no apparent toxicity to the mice [4]
Summary
Cell Lines—Human non-small cell lung adenocarcinoma (NSCLC) cell line A549 and prostate carcinoma cell line PC3 were obtained from the American Type Culture Collection (Manassas, VA).
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