Retinoblastoma Tumor Suppressor Status Is a Critical Determinant of Therapeutic Response in Prostate Cancer Cells

Abstract

The retinoblastoma tumor suppressor protein (RB), a critical mediator of cell cycle progression, is functionally inactivated in the majority of human cancers, including prostatic adenocarcinoma. The importance of RB tumor suppressor function in this disease is evident because 25% to 50% of prostatic adenocarcinomas harbor aberrations in RB pathway. However, no previous studies challenged the consequence of RB inactivation on tumor cell proliferation or therapeutic response. Here, we show that RB depletion facilitates deregulation of specific E2F target genes, but does not confer a significant proliferative advantage in the presence of androgen. However, RB-deficient cells failed to elicit a cytostatic response (compared with RB proficient isogenic controls) when challenged with androgen ablation, AR antagonist, or combined androgen blockade. These data indicate that RB deficiency can facilitate bypass of first-line hormonal therapies used to treat prostate cancer. Given the established effect of RB on DNA damage checkpoints, these studies were then extended to determine the impact of RB depletion on the response to cytotoxic agents used to treat advanced disease. In this context, RB-deficient prostate cancer cells showed enhanced susceptibility to cell death induced by only a selected subset of cytotoxic agents (antimicrotubule agents and a topoisomerase inhibitor). Combined, these data indicate that RB depletion dramatically alters the cellular response to therapeutic intervention in prostate cancer cells and suggest that RB status could potentially be developed as a marker for effectively directing therapy. [Cancer Res 2007;67(13):6192-203]

Rb/E2F4 and Smad2/3 link survivin to TGF-β-induced apoptosis and tumor progression

“…Rb is frequently lost or inactivated in human cancers, for example, 25-50% of prostatic adenocarcinomas have a defective Rb pathway (Jarrard et al, 2002). Rb-depleted prostate cells fail to be growth arrested upon androgen deprivation (Sharma et al, 2007), and survivin deregulation could be one of the major contributing factors based on our current study. Moreover, we show that mutations of both CDE and CHR elements in the survivin promoter actually invert the effect of TGF-b to the one that enhanced this promoter activity, suggesting that defects in such regulation may promote the elevation of survivin by TGF-b and contribute to the oncogenic behavior of TGF-b during tumor progression.…”

Expression of Pituitary Tumor Transforming Gene 1 is an Independent Factor of Poor Prognosis in Localized or Locally Advanced Prostate Cancer Cases Receiving Hormone Therapy

“…These results suggest that disruption of PTTG1 may be one of the major factors contributing to androgen deprivation therapy resistance, and inhibtition of this gene may be a potential therapeutic target in the suppression of prostate cancer progression. We hypothesize that PTTG1 overexpression may be associated with advanced disease that responds poorly to hormone therapy, just as Rb loss was (Sharma et al, 2007). Further studies are necessary to clarify the role of PTTG1 in development and progression of prostate cancer.…”

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

“…[111][112][113] Although a pro-apoptotic function has been reported, 114,115 many studies have found loss of RB function to enhance apoptosis due to inappropriate S-phase control, [116][117][118] causing increased sensitivity to taxanes as well as platinum compounds in different cell lines. 119,120 In contrast, p53-induced apoptosis in response to doxorubicin and combined treatment with metotrexat and 5-fluorouracil has been found to be blunted following RB knockdown in different cell lines. 121 Interestingly, Schmitt et al 41 reported the p53 and the p16/RB pathway to act in concert, inducing senescence and leading to tumour regression in response to cyclophosphamide treatment in a murine model.…”