Long-term cisplatin exposure impairs autophagy and causes cisplatin resistance in human lung cancer cells

Abstract

Cisplatin-based chemotherapy frequently resulted in acquired resistance of cancer cells. The underlying mechanism of such resistance is not fully understood especially the involvement of autophagy and autophagic cell death. This study thus investigated whether an alteration in autophagy could be responsible for cisplatin resistance in the long-term exposure lung carcinoma cells. The cisplatin resistant clone (H460/cis) of H460 cells was established by exposing the cells with gradually increasing concentrations of cisplatin until chemoresistance acquisition was elucidated by MTT, Hoechst 33342 staining and comet assays. Degree of autophagosome formation and level of LC3 marker were evaluated by acridine orange and western blot analysis, respectively. H460/cis cells exhibited irregular shape with ~3-fold resistant to cisplatin-induced apoptosis compared with H460 cells. Proteins analysis for LC3 indicated that the levels of LC3 in resistant cells were significantly lower than those in H460 cells. Moreover, autophagosome formation detected by acridine orange staining was dramatically reduced in the resistant cells, suggesting the role of autophagy in attenuating of cisplatin-induced cell death. Further, co-treatment of cisplatin with autophagy inducer, trifluorperazine, could resensitize H460/cis cells to cisplatin-induced cell death. Our findings reveal the novel mechanisms causing cisplatin resistance in lung carcinoma cells after long-term drug exposure regarding autophagy.

Cytotoxic effects of mithramycin DIG-MSK can depend on the rise of autophagy

“…NFkB and autophagy are deeply linked through a complex 537 network of both transcriptional and transcriptional-independent 538 signals (Pietrocola et al, 2013), and activation of NFkB could be 539 required for optimal autophagic response (Criollo et al, 2012). 540 At odds with several studies that have shown that tumour resis-541 tance to antitumour agents is often associated with the 542 up-regulation of autophagy (White and DiPaola, 2009), our results 543 agree, however, with the growing evidence that autophagy induc-544 tion can also enhance the activity of antitumour agents (Gewirtz,545 2014b; Mansilla et al, 2015;Notte et al, 2011), and it is even 546 the case that reducing autophagy can be a mechanism for acquir-547 ing resistance to chemotherapy (Sirichanchuen et al, 2012). would argue against apoptotic death, yet cells can still be commit-554 ted to dying through necrosis/necroptosis (Fig.…”

Role of Autophagy in Cisplatin Resistance in Ovarian Cancer Cells

“…Accumulating evidence suggests that autophagy plays an important role in chemoresistance (24,25), yet, its involvement in cisplatin resistance in ovarian cancer cells has not been tested. In this regard, a panel of human ovarian cancer cell lines including RMG-1, OV433, OV90, OVCA420, and CAOV3 was treated with 10 or 20 M cisplatin for 24 and 48 h, and changes in LC3-II levels were assessed by Western blot analysis.…”

“…Recent studies indicated that acute cisplatin treatment activates an autophagic response that serves as a survival factor to counteract cisplatin-induced cell death (22,23). In lung cancer cells, autophagy has been suggested to play a role in acquired cisplatin resistance (24,25). However, the role of autophagy in cisplatin resistance in ovarian cancer cells has not been determined.…”

The BH3 mimetic S1 induces endoplasmic reticulum stress-associated apoptosis in cisplatin-resistant human ovarian cancer cells although it activates autophagy

“…It was reported that autophagy activation mediates apoptosis in apoptosis-deficient cells, which is termed autophagic cell death (37,38). However, when cells with normal apoptosis receive a specific stimulation, activation of autophagy protects cells by inhibiting apoptosis (39)(40)(41)(42)(43), and this protective autophagy is activated in a time-dependent manner (44), suggesting that autophagy activation may be involved in the survival and death of SKOV3/ DDP cells. Combined treatment with 3-MA and S1 reduced cell survival compared with S1 treatment alone, demonstrating that autophagy activation facilitated drug-resistant cell resistance to drug stimulation.…”