Mechanism of G1-like arrest by low concentrations of paclitaxel: next cell cycle p53-dependent arrest with sub G1 DNA content mediated by prolonged mitosis.
Paclitaxel (PTX) and other microtubule inhibitors cause mitotic arrest. However, low concentrations of PTX (low PTX) paradoxically cause G1 arrest (without mitotic arrest). Here, we demonstrated that unexpectedly, low PTX did not cause G1 arrest in the first cell cycle and did not prevent cells from passing through S phase and entering mitosis. Mitosis was prolonged but cells still divided, producing either two or three cells (tripolar mitosis), thus explaining a sub G1 peak caused by low PTX. Importantly, sub G1 cells were viable and non-apoptotic. Some cells fused back and then progressed to mitosis, frequently producing three cells again before becoming arrested in the next cell-cycle interphase. Thus, low PTX caused postmitotic arrest in second and even the third cell cycles. By increasing concentration of PTX, tripolar mitosis was transformed to mitotic slippage, thus eliminating a sub G1 peak. Time-lapse microscopy revealed that prolonged mitosis ensured a p53-dependent postmitotic arrest. We conclude that PTX directly affects cells only in mitosis and the duration of mitosis determines cell fate, including p53-dependent G1-like arrest.
Demidenko
Z N
ZN
Oncotarget, Ordway Research Institute, Albany, NY, USA.
Kalurupalle
S
S
Hanko
C
C
Lim
C-u
CU
Broude
E
E
Blagosklonny
M V
MV
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000032:analysis*; D004317:Doxorubicin / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D000972:Antineoplastic Agents, Phytogenic; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D004247:DNA; D017239:Paclitaxel