Studies of Non-Protective Autophagy Provide Evidence that Recovery from Therapy-Induced Senescence is Independent of Early Autophagy

Abstract

Autophagy and senescence, predominant responses that may dictate cell fate after chemotherapy or radiation, often occur in tandem. Cells in states of senescence and/or autophagy are frequently growth arrested. We have previously reported that tumor cells induced into senescence by therapy can re-emerge from the growth-arrested state, a phenomenon termed proliferative recovery. The current work shows that, while tumor cells collaterally induced into senescence and autophagy by etoposide, doxorubicin, or radiation undergo proliferative recovery, neither pharmacological nor genetic inhibition of early autophagy alter the extent of senescence or the ability of cells to recover from senescence. These findings confirm and extend our previous observations, essentially dissociating senescence from autophagy, and further indicate that re-emergence from senescence does not appear to be facilitated by or dependent on autophagy. Our results also provide additional evidence for the promotion of the non-protective form of autophagy by both chemotherapeutic drugs and radiation, which may complicate current efforts to inhibit autophagy for therapeutic benefit.

Escape From Cisplatin-Induced Senescence of Hypoxic Lung Cancer Cells Can Be Overcome by Hydroxychloroquine

“…Therefore, here, we focused on effect of autophagy inhibition on escaping of cancer cells from senescence in hypoxia. In a recent study by Saleh and coworkers, neither shRNAs against ATG5 nor BAF A1/HCQ treatment prior to the subsequent exposure to chemotherapeutics or radiation affected ability of cancer cells to induce senescence or recover from it (91). In line, here, we showed that siRNAs against: ATG5, ATG7, or Beclin1 introduced to normoxic or hypoxic lung cancer cells prior to CIS treatment, did not changed their ability to induce senescence or senescence escaping.…”

The Roles of Autophagy and Senescence in the Tumor Cell Response to Radiation

“…Recently published studies from our laboratory utilizing multiple cytotoxic therapies and multiple cell lines demonstrated senescence induction and proliferative recovery independent of autophagy when the autophagy is ''nonprotective'' in function (92). Furthermore, we observed that autophagy inhibition did not alter the extent of senescence induction or recovery in HCT116 colorectal carcinoma cells exposed to 4 Gy.…”

The BET inhibitor/degrader ARV-825 prolongs the growth arrest response to Fulvestrant + Palbociclib and suppresses proliferative recovery in ER-positive breast cancer

“…Conventionally, most preclinical, and clinical studies designed to evaluate the effect of autophagy inhibition involve the addition of the pharmacological autophagy inhibitors concurrently or as a pre-treatment to therapy ( 41 , 43 , 44 ). Preliminary experiments (not shown) suggested the possibility that a more delayed approach to autophagy inhibition might prove to be a more effective sensitization strategy.…”

“…Consistent with the lack of sensitization, pharmacological autophagy inhibition did not significantly promote apoptotic cell death by the combination of the antiestrogen and CDK 4/6 inhibitor (Figure 3G). Conventionally, most preclinical, and clinical studies designed to evaluate the effect of autophagy inhibition involve the addition of the pharmacological autophagy inhibitors concurrently or as a pre-treatment to therapy (41,43,44). Preliminary experiments (not shown) suggested the possibility that a more delayed approach to autophagy inhibition might prove to be a more effective sensitization strategy.…”