National Centre for Cell Science, Pune, India.
Cancer Sci. 2010 May;101(5):1186-93. doi: 10.1111/j.1349-7006.2010.01516.x. Epub 2010 Jan 28.
Due to substantial technical improvements, clinical application of heat as a co-adjuvant in cancer treatment is acquiring new interest. The effect of hyperthermia on hepatoma cell lines Hep3B (p53 defective) and HepG2 (p53 wild type) when investigated led to an interesting observation that Hep3B cells are more susceptible to heat stress than HepG2 cells. In addition, heat-induced carboplatin resistance was observed in HepG2 cells only. To investigate the reasons, heat shock response was explored and it was observed that heat stress augmented heat shock protein 70 (Hsp70) expression levels in HepG2 and not in Hep3B cells. Furthermore, in HepG2 cells, induced Hsp70 is regulated by both p53 and heat shock transcription factor 1 (HSF1) wherein HSF1 levels are modulated by p53. The data implies that Hep3B are more susceptible to death upon heat stress than HepG2 cells because of non-induction of Hsp70. In addition, it was observed that inhibition of heat-induced p53/HSF1 diminishes Hsp70 levels, thereby restoring the sensitivity of heat-stressed HepG2 cells to carboplatin-triggered cell death. Collectively, the present study establishes interplay of p53, HSF1, and Hsp70 upon heat stress in HepG2 cells and also defines novel strategies to overcome constraints of utility of hyperthermia in cancer therapy through p53/HSF1-targeted therapeutic intervention.
由于技术的重大改进，热作为癌症治疗辅助手段的临床应用正在获得新的关注。对肝癌细胞系 Hep3B（p53 缺陷）和 HepG2（p53 野生型）进行的高温治疗效果研究得出了一个有趣的观察结果，即 Hep3B 细胞比 HepG2 细胞对热应激更敏感。此外，仅在 HepG2 细胞中观察到热诱导的卡铂耐药性。为了探究原因，研究了热休克反应，观察到热应激增强了 HepG2 细胞而不是 Hep3B 细胞中的热休克蛋白 70（Hsp70）表达水平。此外，在 HepG2 细胞中，诱导的 Hsp70 受到 p53 和热休克转录因子 1（HSF1）的调节，其中 HSF1 水平受 p53 调节。数据表明，由于 Hsp70 未被诱导，Hep3B 细胞在热应激下比 HepG2 细胞更容易死亡。此外，还观察到抑制热诱导的 p53/HSF1 可降低 Hsp70 水平，从而恢复热应激 HepG2 细胞对卡铂触发的细胞死亡的敏感性。综上所述，本研究确立了 p53、HSF1 和 Hsp70 在 HepG2 细胞中受到热应激的相互作用，并确定了通过 p53/HSF1 靶向治疗干预克服高温在癌症治疗中应用限制的新策略。
