MLH1-deficient HCT116 colon tumor cells exhibit resistance to the cytostatic and cytotoxic effect of the poly(A) polymerase inhibitor cordycepin (3′-deoxyadenosine) in vitro

Abstract

Abstract. Cordycepin (3'-deoxyadenosine) is an inhibitor of poly(A) polymerase (PAP), an enzyme crucial to mRNA 3'-end processing, which produces the shortening of poly(A) tails, leading to the destabilization of mRNAs. Cordycepin inhibits proliferation and induces apoptosis in tumor cells, indicating its antitumor activity. Defective 3'-end processing is associated with hypersensitivity to UV treatment. We investigated the effects of cordycepin on proliferation and apoptosis in MLH1-deficient and MLH1-proficient HCT116 colon tumor cells. MLH1 is a DNA mismatch repair (MMR) protein involved in the processing of damaged DNA. Cells with defective MMR show resistance to certain anticancer drugs. The results showed that MLH1-deficient HCT116 cells are 2-fold less sensitive to the cytostatic effect of cordycepin, as compared to MLH1-proficient cells. This reduced sensitivity to cordycepin in MLH1-deficient cells was associated with reduced upregulation of the cell cycle inhibitor p21. MLH1-deficient cells also exhibited reduced susceptibility to apoptosis upon treatment with cordycepin, as demonstrated by the reduced PARP-1 cleavage. Our findings showed that MLH1-deficient HCT116 colon tumor cells are resistant to the cytostatic and cytotoxic effect of cordycepin, indicating a possible involvement of MMR in mRNA polyadenylation. The findings also suggest that cordycepin is not suitable to therapeutically encounter tumor cells lacking MLH1 expression.

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“…[42][43][44][45][46] Using these approaches, we analyzed the consequences of VUS function in CRC cell line models in which no wt copy of each affected gene was present. We transfected plasmids expressing the MSH2 series VUS into LoVo cells, 47 the MLH1 series into HCT116 cells, 48 and the PMS2 series into Vaco481 cells 49 (Fig S2 and S3). In the absence of endogenous wt forms of each protein, the protein expression patterns for each VUS were generally similar to those observed in the HEK293 cells (Fig.…”

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“…Also they noted that cells with defective MMR function showed resistance to certain anticancer drugs. So Imesch et al [6] found that MLH1-deficient tumor cells exhibited reduced susceptibility to apoptosis upon treatment with cordycepin, as compared to MLH1-proficient tumor cells.…”

“…Describing mechanism of Cordycepin (3'-deoxyadenosine) cytotoxic effect, Imesch et al [6] researched Cordycepin cytotoxic effect studying both transcription processes, as an inhibitor of Poly (A) Polymerase (PAP), and DNA replication, as MLH1-one of the five DNA Mismatch Repair (MMR) proteins, i.e., processes involved in G2/M phases of cellular cycle. Also they noted that cells with defective MMR function showed resistance to certain anticancer drugs.…”

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“…Also they noted that cells with defective MMR function showed resistance to certain anticancer drugs. So Imesch P, et al [25] found that MLH1-deficient tumor cells exhibited reduced susceptibility to apoptosis upon treatment with cordycepin, as compared to MLH1-proficient tumor cells.…”

“…Describing mechanism of cordycepin (3'-deoxyadenosine) cytotoxic effect, Imesch P, et al [25] found that cordycepin cytotoxic effect via study both transcription processes as an inhibitor of poly(A) polymerase (PAP) and DNA replication focused on MLH1 [one of the five DNA mismatch repair (MMR) proteins], i.e. processes which operate in G2/M phases of cellular cycle.…”