Molecular determinants of terminal growth arrest induced in tumor cells by a chemotherapeutic agent

Abstract

Treatment with chemotherapy or radiation is not invariably cytotoxic to all tumor cells. Some of the cells that survive treatment recover and resume proliferation, whereas others undergo permanent growth arrest. To understand the nature of treatment-induced terminal growth arrest, colon carcinoma cells were exposed to doxorubicin, and surviving cells were separated into proliferating and growth-arrested populations.

A nuclear budding mechanism in transiently arrested cells generates drug-sensitive and drug-resistant cells

“…Evidence is accumulating that senescence may play a key role in chemotherapy outcome [3,12,22]. Low doses of doxorubicin are a well-known inductor of Page 10 of 28 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 10 senescence in HCT116 cells containing wild-type 53 [3,12].…”

“…Mitotic catastrophe occurs in tumor cells treated with various antitumour drugs or radiation [7,13,14,[16][17][18][19][20][21]. These antitumour agents can also limit tumor growth through accelerated senescence arrest [10,12,13,22]. Mitotic catastrophe occurs as a 3 consequence of the uncoupling of the onset of mitosis from DNA replication, but how the resulting lethality is regulated is not completely known.…”

“…Senescence may also follow mitotic catastrophe if polyploid cells are arrested in G1 or G2 after mitotic catastrophe [13,24], but the arrest is not permanent when, for example, cells lack p53 function, or the p53 and p21 WAF1 protein levels decrease after treatment with certain drugs [7,11,13,21,22,25], or as a result of alterations in the phosphorilation of Chk1 [19]. Therefore, cells can re-enter the cell cycle, increasing their polyploidy before they eventually die.…”

Loss of p21Sdi1 expression in senescent cells after DNA damage accompanied with increase of miR-93 expression and reduced p53 interaction with p21Sdi1 gene promoter

“…p21 is involved in the Ras G12V -induced senescence in different human cells; inhibition of p21 expression results in Ras G12V -resistant growth in BJ foreskin fibroblasts [10] and LF1 human lung fibroblasts [11]. Treatment of various human cells with low dose doxorubicin (200 ng/ml) also induces growth arrest with high expressions of p53 and p21 [12]. Increased p53 in response to genotoxic damage temporally regulates selective binding to p21 and MDM2 promoters; p21 induces growth arrest with DNA damage repair, whereas MDM2 degrades p53 in human cells.…”

From fever to immunity: A new role for IGFBP‐6?

“…Overall, these interactions could be part of a mechanism by which IGFBP‐6 regulates apoptosis. Moreover, it could be implicated in other anti‐tumoural effects of IGFBP‐6, such as senescence 53, 54…”