title: GADD45α modulates curcumin sensitivity through c-Abl- and JNK-dependent signaling pathways in a mismatch repair-dependent manner.
abstract: Colorectal cancer is a critical health concern because of its incidence as the third most prevalent cancer in the world. Currently, 5-fluorouracil (5-FU), 6-thioguanine, and certain other genotoxic agents are mainstays of treatment; however, patients often die due to emergence of resistant population. Curcumin, a bioactive compound derived from the dietary turmeric (Curcuma longa) is an effective anticancer, anti-inflammatory, and antioxidant agent. Previously, we reported that human colorectal cancer cell lines compromised for mismatch repair (MMR) function exhibit heightened sensitivity to curcumin due to sustained curcumin-induced unrepaired DNA damage compared to proficient population counterparts. In this report, we show that the protein levels of gadd45α, whose transcript levels are increased during DNA damage and stress signals, are upregulated following curcumin treatment in a dose- and time-dependent manner. We further observed that cells compromised for Mlh1 function (HCT116 + Ch2) displayed ~twofold increased GADD45α upregulation compared to similarly treated proficient counterparts (HCT116 + Ch3). Similarly, suppression of Mlh1 using ShRNA increased GADD45α upregulation upon curcumin treatment. On the other hand, suppression of GADD45α using SiRNA-blocked curcumin-induced cell death induction in Mlh1-deficient cells. Moreover, inhibition of Abl through ST571 treatment and its downstream effector JNK through SP600125 treatment blocked GADD45α upregulation and cell death triggered by curcumin. Collective results lead us to conclude that GADD45α modulates curcumin sensitivity through activation of c-Abl > JNK signaling in a mismatch repair-dependent manner.
authors.affiliation: Department of Biochemistry & Molecular Biology, Pondicherry University, RV Nagar, Puducherry, 605014, India.
authors.forename: Hemanth
authors.initials: H
authors.lastname: Naick
authors.affiliation: Pittsburgh Cancer Institute, Pittsburgh, PA, 15261, USA.
authors.forename: Shunqian
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Biochemistry & Molecular Biology, Pondicherry University, RV Nagar, Puducherry, 605014, India. baskaran.rajasekaran@gmail.com.
authors.forename: R
authors.initials: R
authors.lastname: Baskaran
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D020137:Base Pair Mismatch; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000473:pathology; D003474:Curcumin / Q000494:pharmacology*; D004260:DNA Repair; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D009687:Nuclear Proteins / Q000502:physiology*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D000097642:GADD45 Proteins
chemical_list: D053148:Caspase 3; D053453:Caspase 9; D018797:Cell Cycle Proteins; D003474:Curcumin; D048670:MAP Kinase Kinase 4; D009687:Nuclear Proteins; D016315:Proto-Oncogene Proteins c-abl; C439070:GADD45A protein, human; D000097642:GADD45 Proteins
keywords: Apoptosis; C-Abl; Curcumin; GADD45; JNK
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