Taxol-induced unfolded protein response activation in breast cancer cells exposed to hypoxia: ATF4 activation regulates autophagy and inhibits apoptosis.
Understanding the mechanisms responsible for the resistance against chemotherapy-induced cell death is still of great interest since the number of patients with cancer increases and relapse is commonly observed. Indeed, the development of hypoxic regions as well as UPR (unfolded protein response) activation is known to promote cancer cell adaptive responses to the stressful tumor microenvironment and resistance against anticancer therapies. Therefore, the impact of UPR combined to hypoxia on autophagy and apoptosis activation during taxol exposure was investigated in MDA-MB-231 and T47D breast cancer cells. The results showed that taxol rapidly induced UPR activation and that hypoxia modulated taxol-induced UPR activation differently according to the different UPR pathways (PERK, ATF6, and IRE1α). The putative involvement of these signaling pathways in autophagy or in apoptosis regulation in response to taxol exposure was investigated. However, while no link between the activation of these three ER stress sensors and autophagy or apoptosis regulation could be evidenced, results showed that ATF4 activation, which occurs independently of UPR activation, was involved in taxol-induced autophagy completion. In addition, an ATF4-dependent mechanism leading to cancer cell adaptation and resistance against taxol-induced cell death was evidenced. Finally, our results demonstrate that expression of ATF4, in association with hypoxia-induced genes, can be used as a biomarker of a poor prognosis for human breast cancer patients supporting the conclusion that ATF4 might play an important role in adaptation and resistance of breast cancer cells to chemotherapy in hypoxic tumors.
Laboratory of Biochemistry and Cellular Biology (URBC), NAmur Research Institute for Life Science (NARILIS), University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium.
Annick
A
Notte
Laboratory of Biochemistry and Cellular Biology (URBC), NAmur Research Institute for Life Science (NARILIS), University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium.
Magali
M
Rebucci
Laboratory of Biochemistry and Cellular Biology (URBC), NAmur Research Institute for Life Science (NARILIS), University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium.
Maude
M
Fransolet
Laboratory of Biochemistry and Cellular Biology (URBC), NAmur Research Institute for Life Science (NARILIS), University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium.
Edith
E
Roegiers
Laboratory of Biochemistry and Cellular Biology (URBC), NAmur Research Institute for Life Science (NARILIS), University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium.
Marie
M
Genin
Laboratory of Biochemistry and Cellular Biology (URBC), NAmur Research Institute for Life Science (NARILIS), University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium.
Celine
C
Tellier
Laboratory of Biochemistry and Cellular Biology (URBC), NAmur Research Institute for Life Science (NARILIS), University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium.
Kassandra
K
Watillon
Laboratory of Biochemistry and Cellular Biology (URBC), NAmur Research Institute for Life Science (NARILIS), University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium.
Antoine
A
Fattaccioli
Laboratory of Biochemistry and Cellular Biology (URBC), NAmur Research Institute for Life Science (NARILIS), University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium.
Thierry
T
Arnould
Laboratory of Biochemistry and Cellular Biology (URBC), NAmur Research Institute for Life Science (NARILIS), University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium. Electronic address: carine.michiels@unamur.be.
Carine
C
Michiels
D051701:Activating Transcription Factor 4 / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D056811:Unfolded Protein Response / Q000187:drug effects*
C497109:ATF4 protein, human; D051701:Activating Transcription Factor 4; D017239:Paclitaxel
ATF4; Apoptosis; Autophagy; Breast cancer; Hypoxia; UPR