Trans-chalcone increases p53 activity via DNAJB1/HSP40 induction and CRM1 inhibition

Gabriel Silva; Mozart Marins; Nadda Chaichanasak; Yongdae Yoon; Ana Lúcia Fachin; Vitor Caressato Pinhanelli; Luis Octávio Regasini; Mariana Bastos Dos Santos; Gabriela Miranda Ayusso; Beatriz de Carvalho Marques; Wells W Wu; Je-Nie Phue; Rong-Fong Shen; Seung Joon Baek

doi:10.1371/journal.pone.0202263

Trans-chalcone increases p53 activity via DNAJB1/HSP40 induction and CRM1 inhibition

PLoS One. 2018 Aug 17;13(8):e0202263. doi: 10.1371/journal.pone.0202263. eCollection 2018.

Authors

Gabriel Silva¹, Mozart Marins^{1

2}, Nadda Chaichanasak³, Yongdae Yoon³, Ana Lúcia Fachin^{1

2}, Vitor Caressato Pinhanelli¹, Luis Octávio Regasini⁴, Mariana Bastos Dos Santos⁴, Gabriela Miranda Ayusso⁴, Beatriz de Carvalho Marques⁴, Wells W Wu⁵, Je-Nie Phue⁵, Rong-Fong Shen⁵, Seung Joon Baek³

Affiliations

¹ Biotechnology Unit, University of Ribeirão Preto, Ribeirão Preto, São Paulo, Brazil.
² Medicine School, University of Ribeirão Preto, Ribeirão Preto, São Paulo, Brazil.
³ Laboratory of Signal Transduction, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, Republic of Korea.
⁴ Department of Chemistry and Environmental Chemistry, São Paulo State University (UNESP), São Paulo, Brazil.
⁵ Facility for Biotechnology Resources, CBER, Food and Drug Administration, Silver Spring, Maryland, United States of America.

Abstract

Naturally-occurring chalcones and synthetic chalcone analogues have been demonstrated to have many biological effects, including anti-inflammatory, anti-malarial, anti-fungal, and anti-oxidant/anti-cancerous activities. Compared to other chalcones, trans-chalcone exhibits superior inhibitory activity in cancer cell growth as shown via in vitro assays, and exerts anti-cancerous effects via the activation of the p53 tumor suppressor protein. Thus, characterization of the specific mechanisms, by which trans-chalcone activates p53, can aid development of new chemotherapeutic drugs that can be used individually or synergistically with other drugs. In this report, we found that trans-chalcone modulates many p53 target genes, HSP40 being the most induced gene in the RNA-Seq data using trans-chalcone-treated cells. CRM1 is also inhibited by trans-chalcone, resulting in the accumulation of p53 and other tumor suppressor proteins in the nucleus. Similar effects were seen using trans-chalcone derivatives. Overall, trans-chalcone could provide a strong foundation for the development of chalcone-based anti-cancer drugs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 3 / metabolism
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Caspase 3 / metabolism
Caspase 7 / metabolism
Cell Line, Tumor
Cell Nucleus / drug effects
Cell Nucleus / metabolism
Chalcone / chemistry
Chalcone / pharmacology*
Exportin 1 Protein
Growth Differentiation Factor 15 / metabolism
HSP40 Heat-Shock Proteins / metabolism*
Humans
Karyopherins / antagonists & inhibitors
Karyopherins / metabolism*
Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
Receptors, Cytoplasmic and Nuclear / metabolism*
Signal Transduction / drug effects
Transcription, Genetic / drug effects
Tumor Suppressor Protein p53 / metabolism*

Substances

ATF3 protein, human
Activating Transcription Factor 3
Antineoplastic Agents
DNAJB1 protein, human
GDF15 protein, human
Growth Differentiation Factor 15
HSP40 Heat-Shock Proteins
Karyopherins
Receptors, Cytoplasmic and Nuclear
Tumor Suppressor Protein p53
Chalcone
CASP3 protein, human
CASP7 protein, human
Caspase 3
Caspase 7

Grants and funding

This work was supported by a grant from Fundação de Amparo à Pesquisa do Estado de São Paulo (grant no.: 14/15307-7). This work was also supported by the Research Resettlement Fund for the new faculty, the Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research Center, Seoul National University, and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2018R1A2B2002923) to SJB. GS holds a scholarship via a grant from the CAPES Foundation—an agency under the Ministry of Education of Brazil (grant no.: BEX 3159/14-0). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.