HIF-1α and rapamycin act as gerosuppressant in multiple myeloma cells upon genotoxic stress

Abstract

Multiple myeloma (MM) is still an incurable hematological malignancy. Despite recent progress due to new anti-myeloma agents, the pathology is characterized by a high frequency of de novo or acquired resistance. Delineating the mechanisms of MM resistance is essential for therapeutic advances. We previously showed that long-term genotoxic stress induces the establishment of a senescence-associated secretory phenotype, a pro-inflammatory response that favors the emergence of cells with cancer stem-like properties. Here, we studied the short-term response of MM cells following treatment with various DNA damaging agents such as the energetic C-ion irradiation. MM cells are highly resistant to all treatments and do not enter apoptosis after they arrest cycling at the G2 phase. Although the DNA damage response pathway was activated, DNA breaks remained chronically in damaged MM cells. We found, using a transcriptomic approach that RAD50, a major DNA repair gene was downregulated early after genotoxic stress. In two gerosuppression situations: induction of hypoxia and inhibition of the mammalian target of rapamycin (mTOR) pathway, we observed, after the treatment with a DNA damaging agent, a normalization of RAD50 expression concomitant with the absence of cell cycle arrest. We propose that combining inhibitors of mTOR with genotoxic agents could avoid MM cells to senesce and secrete proinflammatory factors responsible for cancer stem-like cell emergence and, in turn, relapse of MM patients.

A predicted risk score based on the expression of 16 autophagy‑related genes for multiple myeloma survival

“…Hypoxia, a central characteristic for cancer incidence and progression, occurs when most types of cancer are evolving (59)(60)(61)(62)(63)(64). HIF1A is a hypoxia-inducible factor, and constitutive expression of HIF1A in MM indicates that suppression of HIF1A-mediated transcription could become a favorable target for MM (65)(66)(67)(68). For instance, chetomin, an inhibitor of the HIF1A/p300 interaction, can inhibit tumor cell growth of MM (69).…”

Cyclin D1 targets hexokinase 2 to control aerobic glycolysis in myeloma cells

“…GFP expression was checked regularly by flow cytometry. Cells were treated overnight with 300 μM CoCl 2 (Sigma-Aldrich, Saint-Louis, MO), as previously described 34 , to mimic hypoxia and stabilize HIF1α.…”

Rapamycin, proliferation and geroconversion to senescence

“…Rapamycin similarly preserved RPP during cell cycle arrest caused by pharmacologic inhibitors of CDK4/6, DNA damaging drugs, HDACi and phorbol ester [29,58,[65][66][67]. Suppression of senescence by rapamycin was further confirmed in vitro and in vivo [26,40,[62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81]. In addition to rapamycin, everolimus and ridaforolimus (two rapalogs), pan-mTOR inhibitors, nutlin-3a (a p53-inducer), hypoxia and contact inhibition all inhibit mTOR and thus maintain RPP in arrested cells [2,[32][33][34]58,[82][83][84][85][86].…”