Shimozawa Makoto, Anzai Sakiho, Satow Reiko, Fukami Kiyoko
Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Tokyo 192-0392, Japan.
Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Hachioji-shi, Tokyo 192-0392, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo 100-0004, Japan.
Biochem Biophys Res Commun. 2017 Jul 8;488(4):578-583. doi: 10.1016/j.bbrc.2017.05.098. Epub 2017 May 18.
Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Kirsten rat sarcoma viral oncogene homolog (KRAS) is frequently mutated in CRC, and KRAS mutations promote cell motility, growth, and survival. We previously revealed that the expression of phospholipase C (PLC) δ1, one of the most basal PLCs, is down-regulated in colon adenocarcinoma, and that the KRAS signaling pathway suppresses PLCδ1 expression. Although recent studies revealed that KRAS mutations activate autophagy in cancer cells, a relation between PLCδ1 and autophagy remains unclear. Here, we found that PLCδ1 overexpression suppresses the formation of autophagosomes, which are key structures of autophagy, whereas endogenous PLCδ1 knockdown increases autophagosome formation in CRC cells. We also showed that PLCδ1 overexpression promotes cell death under nutrient deprivation. Furthermore, PLCδ1 overexpression suppresses the autophagy induced by the anti-cancer drug oxaliplatin and promotes cell death under oxaliplatin treatment. These data suggest that PLCδ1 negatively regulates autophagy, and PLCδ1 suppression contributes to the tolerance of CRC cells harboring KRAS mutations to nutrient deprivation and anti-cancer drug treatment.
结直肠癌（CRC）是全球癌症相关死亡的主要原因之一。 Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）在CRC中经常发生突变，并且KRAS突变促进细胞运动、生长和存活。我们之前发现，磷脂酶C（PLC）δ1（最基础的PLC之一）的表达在结肠腺癌中下调，并且KRAS信号通路抑制PLCδ1的表达。尽管最近的研究表明KRAS突变可激活癌细胞中的自噬，但PLCδ1与自噬之间的关系仍不清楚。在这里，我们发现PLCδ1过表达抑制自噬体的形成，自噬体是自噬的关键结构，而内源性PLCδ1敲低则增加CRC细胞中自噬体的形成。我们还表明，PLCδ1过表达在营养剥夺条件下促进细胞死亡。此外，PLCδ1过表达抑制抗癌药物奥沙利铂诱导的自噬，并在奥沙利铂治疗下促进细胞死亡。这些数据表明，PLCδ1负向调节自噬，并且PLCδ1的抑制有助于携带KRAS突变的CRC细胞对营养剥夺和抗癌药物治疗的耐受性。
