MCL-1 dependency of cisplatin-resistant cancer cells

Judith Michels, Florine Obrist, Ilio Vitale, Delphine Lissa, Pauline Garcia, Parviz Behnam-Motlagh, Kimitoshi Kohno, Gen Sheng Wu, Catherine Brenner, Maria Castedo, Guido Kroemer

Research output: Contribution to journalArticle

Abstract

The selection of human cancer cell lines in cis-diamminedichloroplatinum(II) (CDDP, best known as cisplatin) is accompanied by stereotyped alterations that contribute to the acquisition of a CDDP-resistant state. Thus, CDDP resistance often leads to the upregulation of the DNA repair enzyme poly (ADP-ribose) polymerase-1 (PARP1) with the consequent intracellular accumulation of poly (ADP-ribose) (PAR)-modified proteins. Here we report another frequent alteration accompanying CDDP resistance, namely upregulation of the antiapoptotic BCL-2 family protein MCL-1. Six out of 8 CDDP resistant cancer cell lines manifested an increase in MCL-1 protein expression level, while only a minority of cell lines overexpressed BCL-2 or BCL-XL. BCL-XL was decreased in six out of 8 cancer cell lines. Importantly, MCL-1 overexpressing, CDDP resistant cells appear to be 'addicted' to MCL-1 because they died upon depletion of MCL-1 by RNA interference or pharmacological inhibition of MCL-1 expression by the BH3 mimetic obatoclax. Knockdown of PARP1 did not succeed in reducing MCL-1 expression, while depletion or inhibition of MCL-1 failed to affect the activity of PARP1. Hence, the two resistance mechanisms are not linked to each other by a direct cause-effect relationship. Importantly, CDDP-resistant, MCL-1 overexpressing human non-small cell lung cancers responded to monotherapy with obatoclax in vivo, in xenotransplanted mice, underscoring the probable therapeutic relevance of these findings.

Original languageEnglish
Pages (from-to)55-61
Number of pages7
JournalBiochemical Pharmacology
Volume92
Issue number1
DOIs
Publication statusPublished - Nov 1 2014

Keywords

  • Apoptosis
  • Chemoresistance
  • MCL-1
  • Obatoclax
  • PARP1

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry
  • Medicine(all)

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