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Abstract

Head and neck squamous cell carcinoma (HNSCC) is treated with cisplatin (CDDP) and radiotherapy (RT), and distinct results are observed among patients with similar clinicopathological aspects. This prospective study aimed to investigate whether MLH1 c.-93G>A (rs1800734), MSH2 c.211+9C>G (rs2303426), MSH3 c.3133G>A (rs26279), EXO1 c.1765G>A (rs1047840), and EXO1 c.2270C>T (rs9350) single nucleotide polymorphisms (SNPs) of the mismatch repair (MMR) pathway change side effects and response rate of 90 HNSCC patients treated with CDDP and RT. DNA from peripheral blood was analyzed by PCR-based methods to obtain genotypes. It was observed 4.27-fold and 4.69-fold increased risks of presenting pronounced nephrotoxicity with treatment in patients with MSH3 GG and EXO1 rs9350 CC genotypes compared with patients with GA or AA and CT or TT genotypes, respectively. MSH3 GG or GA and GT haplotype of EXO1 rs1047840 and rs9350 SNPs conferred to patients 10.29 and 4.00 more chances of presenting pronounced ototoxicity after treatment than MSH3 AA genotype and other EXO1 haplotypes, respectively. Patients with EXO1 rs1047840 GA or AA genotype and AC haplotype of EXO1 rs1047840 and rs9350 SNPs had both 9.55-fold increased risks of achieving partial response or stable disease instead of complete remission after treatment than patients with EXO1 GG genotype and other EXO1 haplotypes, respectively. For the first time, our data show preliminary indication that inherited alterations of DNA MMR pathway, related to MSH3 rs26279, EXO1 rs1047840 and EXO1 rs9350 SNPs, modify toxicity and response to chemoradiation in HNSCC, and may contribute to future personalized treatment of patients.

Phosphorylation of cell cycle and apoptosis regulatory protein-1 by stress activated protein kinase P38γ is a novel mechanism of apoptosis signaling by genotoxic chemotherapy

“…A list of selected target proteins that interacted with CARP-1 (614–638) peptide is shown in Table 3 . Of note is the fact that CCAR2 (DBC1; a CARP-1 paralog), Filamin C, and BRAF have been demonstrated to interact with CARP-1 in prior studies by us and others ( 7 , 16 , 26 , 27 ). CARP-1 (614–638) peptide also interacted with MAPK12/p38γ suggesting that MAPK12/p38γ could be the kinase among the MAPKs noted in Table 1 above that functions to transduce CARP-1 T 627 phosphorylation by ADR.…”

“…Our prior and on-going studies have indicated that DNA damage-inducing genotoxic agents such as ADR, Cisplatin, or CFM compounds promote apoptosis in part by stimulating levels of CARP-1, phosphorylated SAPKs p38α/β and JNK1/2, cleaved PARP, and activated caspases-3, and -8 ( 7 – 16 ). Knockdown of CARP-1 or pharmacological inhibition of caspase-3 and -8 abrogated apoptosis by ADR, CFM compounds, or EGFR TKIs ( 7 , 9 , 11 , 14 , 16 ). Moreover, expression of CARP-1 with in-frame deletion of amino acids 600-650 (CARP-1 Δ600-650) also abrogated apoptosis by ADR and CFM compound ( 11 ).…”

“…Next, we treated wild-type MDA-MB-468 HBC cells with ADR, pan-p38 inhibitor Doramapimod ( 28 ), JNK inhibitor JNK-1N8 ( 11 , 29 ), or ERK inhibitor Ulixertinib ( 16 , 30 ) as single agents or ADR in combination with respective MAPK/SAPK inhibitor as detailed in Methods. The cell lysates were analyzed by WB for presence of T 627 phosphorylated CARP-1.…”

“…A total of 504 tumor specimens with non-identifiable patient treatment and survival outcome were analyzed. Immunostaining of the TMA slides was carried out with anti-phospho-CARP-1 antibodies (1:1,500 dilution) as well as with total CARP-1 (α2) antibodies essentially following methods described by us before ( 8 , 9 , 13 , 14 , 16 ). Staining for phospho-CARP was scored by Dr. Edi Levi, Staff Pathologist and Associate Chief of Staff (Research), John D. Dingell VA Medical Center, Detroit, MI.…”

“…CARP-1 functions to transduce growth and survival signaling by steroid/thyroid receptor superfamily members, Wnt/β-catenin, notch receptors, APC/C E3 ligase, and NF-κB, as well as regulates endocrine differentiation ( 2 – 8 ). CARP-1 also transduces apoptosis signaling by a variety of genotoxic chemotherapies such as Adriamycin (Doxorubicin), Etoposide, Cisplatin, and CFM experimental compounds, as well as by the EGFR TKIs gefitinib, Erlotinib, and Osimertinib ( 7 – 16 ).…”