The pro-apoptotic role of autophagy in breast cancer

Abstract

Background:Autophagy is a catabolic process that has a vital role in cancer progression and treatment. Current chemotherapeutic agents, which target autophagy, result in growth inhibition in many cancer types. In this study, we examined the role of autophagy in breast cancer (BCa) patients as well as BCa cell lines.Methods:Tissue microarray was used to detect the expression of an autophagy marker, LC3B in BCa patients (normal/hyperplasia=8; grade-I=15, grade-II=84, and grade-III=27) and BCa cell lines. To modulate the activation of autophagy, we used novel herbal compound nimocinol acetate (NA) in BCa cell lines and the anticancer activity was measured by phenotypic and molecular analysis.Results:LC3B is highly expressed in tumours as compared with normal tissues. Activation of LC3B in NA-treated BCa (MCF-7 and MDA-MB-231) cells was evident as compared with other autophagy makers. Further, our results confirmed that NA-transcriptionally regulates LC3B (as confirmed by mRNA levels and reporter assay), which resulted in the formation of acidic autophagy vesicles and autolysosomes in BCa cells. Nimocinol acetate inhibited mTOR-mediated pro-survival signalling that resulted in inhibition of growth in BCa cells without affecting normal breast epithelial cells. Downregulation of LC3B expression by siRNA significantly inhibited the anticancer effects of NA in BCa cells.Conclusions:Together, our results suggest that LC3B is highly expressed in BCa tissues and increasing the threshold of LC3B activation dictates the pro-apoptotic function, which in turn, suppresses the growth of BCa cells. Nimocinol acetate could be a potential agent for treatment of BCa.

Targeting the non-canonical roles of PCNA modifies and increases the response to targeted anti-cancer therapy

“…Downregulation of the important autophagic proteins ULK and Beclin-1 often occurs in breast cancer, particularly in TNBC, suggesting that activation of autophagy may be beneficial [44]. Other studies suggest that a molecular switch is deciding the autophagy-mediated fate of the cells, and that increased autophagy above a threshold will force autophagic cell death [44][45][46]. As AEE788 is previously published to induce the pro-survival activity of autophagy [47], the observed increase in autophagic flux in our study could be an attempt to overcome the therapeutic stress.…”

Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer

“…LC3B staining is reported to be generally higher in tumor tissues than in normal tissues. 27,28 In estrogen receptor-negative BC, no association has been found between LC3B expression and androgen receptor expression and HER2 positivity.…”

Synthesis of Psoralidin derivatives and their anticancer activity: first synthesis of Lespeflorin I1

“…11a–e For the experiment, the cells were treated with the dimethyl sulfoxide (DMSO) solution (final concentration of 0.002%) of the synthesized compounds and the cell viability was quantified using the trypan blue exclusion assay. 20 The natural product Psoralidin was used as a positive control and the vehicle (DMSO) as a negative control. Experiments on compound 14–15 and 25–28 showed that none of the compounds was able to carry out a reasonable inhibition of the growth of the cancer cells.…”

“…A collection of supernatants and adherent cells obtained by trypsinization were incubated in 0.4% trypan blue (Corning, Manassas, VA) at 1:1 ratio and pipetted onto a hematocytometer and manually counted under a microscope at ×20 magnification. 20 Psoralidin was used as a positive control and vehicle (DMSO) as a negative control.…”