Abstract

Chemotherapy is the commonly used treatment for advanced lung cancer. However, it produces side effects such as the development of chemoresistance. A possible responsible mechanism may be therapy-induced senescence (TIS). TIS cells display increased senescence-associated β-galactosidase (SA-β-gal) activity and irreversible growth arrest. However, recent data suggest that TIS cells can reactivate their proliferative potential and lead to cancer recurrence. Our previous study indicated that reactivation of proliferation by TIS cells might be related with autophagy modulation. However, exact relationship between both processes required further studies. Therefore, the aim of our study was to investigate the role of autophagy in the senescence-related chemoresistance of lung cancer cells. For this purpose, human and murine lung cancer cells were treated with two commonly used chemotherapeutics: cisplatin (CIS), which forms DNA adducts or docetaxel (DOC), a microtubule poison. Hypoxia, often overlooked in experimental settings, has been implicated as a mechanism responsible for a significant change in the response to treatment. Thus, cells were cultured under normoxic (~19% O2) or hypoxic (1% O2) conditions. Herein, we show that hypoxia increases resistance to CIS. Lung cancer cells cultured under hypoxic conditions escaped from CIS-induced senescence, displayed reduced SA-β-gal activity and a decreased percentage of cells in the G2/M phase of the cell cycle. In turn, hypoxia increased the proliferation of lung cancer cells and the proportion of cells proceeding to the G0/G1 phase. Further molecular analyses demonstrated that hypoxia inhibited the prosenescent p53/p21 signaling pathway and induced epithelial to mesenchymal transition in CIS-treated cancer cells. In cells treated with DOC, such effects were not observed. Of importance, pharmacological autophagy inhibitor, hydroxychloroquine (HCQ) was capable of overcoming short-term CIS-induced resistance of lung cancer cells in hypoxic conditions. Altogether, our data demonstrated that hypoxia favors cancer cell escape from CIS-induced senescence, what could be overcome by inhibition of autophagy with HCQ. Therefore, we propose that HCQ might be used to interfere with the ability of senescent cancer cells to repopulate following exposure to DNA-damaging agents. This effect, however, needs to be tested in a long-term perspective for preclinical and clinical applications.

Highlights

  • Lung cancer remains the leading cause of cancer-related deaths

  • A two-drug regimen based on a platinum derivative and a drug disrupting the microtubule function is most often used in patients with lung cancer

  • To reproduce the cell response to chemotherapy in the natural microenvironment, we investigated the effects of both chemotherapeutic agents under hypoxic conditions

Read more

Summary

Introduction

Lung cancer remains the leading cause of cancer-related deaths. Approximately 85% of all lung cancer cases are nonsmall cell lung cancer (NSCLC) and adenocarcinoma is the most common histological subtype of NSCLC [1, 2]. Despite the development of targeted therapies, platinum-based chemotherapy (CIS or carboplatin) is still a predominant treatment regimen for advanced lung cancer patients. It is combined with other chemotherapeutic drugs: vinorelbine, gemcitabine, or taxanes (DOC or paclitaxel). It has been largely documented that tumor heterogeneity, plasticity, and adaptation may cause TIS cells to escape from senescence and return into an actively reproductive state, leading to cancer recurrence [7, 15,16,17]. The induction of senescence itself seems to be an insufficient endpoint and additional strategies are needed to achieve a better therapeutic response

Objectives
Methods
Results
Discussion
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call