Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Cancer Sci. 2012 Jul;103(7):1272-9. doi: 10.1111/j.1349-7006.2012.02297.x. Epub 2012 May 17.
Pancreatic cancer is one of the deadliest types of cancer. Previously, we showed that hypoxia increases invasiveness through upregulation of Smoothened (Smo) transcription in pancreatic ductal adenocarcinoma (PDAC) cells. Here, we first evaluated whether hypoxia-induced increase in Smo contributes to the proliferation of PDAC cells. We showed that Smo, but not Gli1, inhibition decreases proliferation significantly under hypoxic conditions. To further investigate the effects of Smo on PDAC growth, cell cycle analysis was carried out. Inhibition of Smo under hypoxia led to G(0) /G(1) arrest and decreased S phase. As 5-fluorouracil (5-FU) and gemcitabine, which are first-line drugs for pancreatic cancer, are sensitive to S phase, we then evaluated whether cyclopamine-induced decreased S phase under hypoxia affected the chemosensitivity of 5-FU and gemcitabine in PDAC cells. Cyclopamine treatment under hypoxia significantly decreased chemosensitivity to 5-FU and gemcitabine under hypoxia in both in vitro and in vivo models. In contrast, cis-diamminedichloroplatinum, which is cell cycle-independent, showed significant synergistic effects. These results suggest that hypoxia-induced increase of Smo directly contributes to the proliferation of PDAC cells through a hedgehog/Gli1-independent pathway, and that decreased S phase due to the use of Smo inhibitor under hypoxia leads to chemoresistance in S phase-sensitive anticancer drugs. Our results could be very important clinically because a clinical trial using Smo inhibitors and chemotherapy drugs will begin in the near future.
胰腺癌是最致命的癌症类型之一。此前，我们已经证明，在胰腺导管腺癌（PDAC）细胞中，缺氧通过上调 Smoothened（Smo）转录来增加侵袭性。在这里，我们首先评估了缺氧诱导的 Smo 增加是否有助于 PDAC 细胞的增殖。我们发现，在缺氧条件下，Smo 抑制而非 Gli1 抑制可显著降低细胞增殖。为了进一步研究 Smo 对 PDAC 生长的影响，我们进行了细胞周期分析。在缺氧下抑制 Smo 导致 G0/G1 期停滞并减少 S 期。由于氟尿嘧啶（5-FU）和吉西他滨是胰腺癌的一线药物，对 S 期敏感，因此我们评估了在缺氧下环巴胺诱导的 S 期减少是否会影响 PDAC 细胞中 5-FU 和吉西他滨的化疗敏感性。在体外和体内模型中，缺氧下的环巴胺处理显著降低了缺氧下 5-FU 和吉西他滨的化疗敏感性。相比之下，细胞周期非依赖性顺铂表现出显著的协同作用。这些结果表明，缺氧诱导的 Smo 增加通过 Hedgehog/Gli1 非依赖性途径直接促进 PDAC 细胞的增殖，并且缺氧下使用 Smo 抑制剂导致 S 期减少导致 S 期敏感的抗癌药物的化疗耐药性。我们的结果在临床上可能非常重要，因为一项使用 Smo 抑制剂和化疗药物的临床试验将在不久的将来开始。
