Palbociclib induces activation of AMPK and inhibits hepatocellular carcinoma in a CDK4/6‐independent manner

Abstract

Palbociclib, a CDK4/6 inhibitor, has recently been approved for hormone receptor‐positive breast cancer patients. The effects of palbociclib as a treatment for other malignancies, including hepatocellular carcinoma (HCC), are of great clinical interest and are under active investigation. Here, we report the effects and a novel mechanism of action of palbociclib in HCC. We found that palbociclib induced both autophagy and apoptosis in HCC cells through a mechanism involving 5′ AMP‐activated protein kinase (AMPK) activation and protein phosphatase 5 (PP5) inhibition. Blockade of AMPK signals or ectopic expression of PP5 counteracted the effect of palbociclib, confirming the involvement of the PP5/AMPK axis in palbociclib‐mediated HCC cell death. However, CDK4/6 inhibition by lentivirus‐mediated shRNA expression did not reproduce the effect of palbociclib‐treated cells, suggesting that the anti‐HCC effect of palbociclib is independent of CDK4/6. Moreover, two other CDK4/6 inhibitors (ribociclib and abemaciclib) had minimal effects on HCC cell viability and the PP5/AMPK axis. Palbociclib also demonstrated significant tumor‐suppressive activity in a HCC xenograft model, which was associated with upregulation of pAMPK and PP5 inhibition. Finally, we analyzed 153 HCC clinical samples and found that PP5 expression was highly tumor specific and was associated with poor clinical features. Taken together, we conclude that palbociclib exerted antitumor activity against HCC through the PP5/AMPK axis independent of CDK4/6. Our findings provide a novel mechanistic basis for palbociclib and reveal the therapeutic potential of targeting PP5/AMPK signaling with a PP5 inhibitor for the treatment of hepatocellular carcinoma.

Abemaciclib induces atypical cell death in cancer cells characterized by formation of cytoplasmic vacuoles derived from lysosomes

“…It was reported that CDK4/6 inhibitors induce autophagy 29‐35 . Based on the results described above, we speculated that the prominent vacuole formation in response to abemaciclib might be related to autophagy.…”

“…This observation also supports the idea that a target or targets other than CDK4/6 contribute to lysosomal dysfunction. Several previous studies reported induction of autophagy in response to CDK4/6 inhibitors 29‐34,50 . In this study, we sequentially monitored autophagic flux using fluorescence probe 37 ; this analysis revealed that all 3 CDK4/6 inhibitors tested inhibited autophagic flux at early time points.…”

Therapeutic Evaluation of Palbociclib and Its Compatibility with Other Chemotherapies in Primary and Recurrent Nasopharyngeal Carcinoma

“…All these suggest that autophagy is associated with the cell death induced in cells treated with palbociclib alone or in combination with SAHA. A previous study showed that palbociclib induced autophagy in hepatocellular carcinoma cells in a CDK4/6 independent manner, but through a mechanism involving 5′ AMP-activated protein kinase (AMPK) activation and protein phosphatase 5 (PP5) inhibition (62). Some earlier studies reported HDAC inhibitors could induce caspase-independent autophagic cell death in HeLa and chondrosarcoma (63,64).…”

In vitro study to assess the efficacy of CDK4/6 inhibitor Palbociclib (PD‐0332991) for treating canine mammary tumours

“…Thus, Palbociclib has not only a cytostatic effect but seemingly a potential cytotoxic effect on CMT cells. Although this observation contrasts to that for human BCa cells, which showed no apoptosis after prolonged Palbociclib treatment, cytotoxic potential for the CDK4/6 inhibitor was reported for human glioblastoma, hepatocellular carcinoma and T‐cell acute lymphoblastic leukaemia cells . Wang et al demonstrated that the pro‐apoptotic Palbociclib effect is associated with CDK6 expression in that Palbociclib induces apoptosis in cancer cells with high expression of CDK6, whereas cells with low CDK6 only show cell cycle arrest .…”

“…Thus, CF41 cells apparently resist the cytotoxic mechanisms of Palbociclib longer than P114 cells. Palbociclib induces apoptosis of tumour cells by interfering with enzymes regulating glucose metabolism in T‐ALL cells or activation of AMP‐activated protein kinase in hepatocellular carcinomas . Assuming that Palbociclib also affects the viability of CMT cells through such mechanisms, different susceptibilities of these target enzymes might be responsible for the delayed effect on P114 and CF41 cell viability.…”